Paracetamol (or acetaminophen, N-acetyl-para-aminophenol, C8H9NO2) is a medication with analgesic and antipyretic action widely used both alone and in association with other substances, for example in common over-the-counter preparations for viral forms of cold, or in drugs for the treatment of acute and chronic pain.
It acts on the nervous system by altering the perception of pain by the body mainly through the action on mechanisms controlled by serotonin, opioids and cannabinoids, and lowering body temperature by inhibiting the synthesis of prostaglandins, molecules involved in inflammatory processes.
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What is paracetamol used for
Paracetamol is used to counteract mild to moderate pain associated with headaches, muscle discomfort, menstrual cycle, cold syndromes, sore throat, toothache, backache, arthritis and reactions to vaccinations. It is also used to lower fever.
In combination with aspirin and caffeine, it can also be used to reduce the pain associated with migraine headaches.
Administration and bioavailability
Pure acetaminophen is a white crystalline powder. Paracetamol can be administered through different routes (orally in the form of tablets, chewable tablets, capsules, suspensions, solutions, extended-release tablets or tablets that dissolve in the mouth, or rectally, in the form of suppositories) and has a high bioavailability, which does not undergo important changes, except in cases of chronic liver disease. At the level of the liver, in fact, the molecule is transformed into a metabolite that is toxic to liver tissue. At the doses commonly used, however, the risks of hepatotoxicity are null, so that the use of paracetamol is not contraindicated in pediatric age, nor in pregnancy.
The analgesic effect appears promptly (about 11 minutes) after oral administration and the half-life of the drug is 1-4 hours.
The maximum recommended dose (U.S. Pharmacopoeia) is 4 grams per day and the single dose should not exceed one gram, while the Italian Official Pharmacopoeia recommends the intake of no more than 3 grams per day. Even with the necessary cautions to reduce the dose in subjects with impaired liver function, paracetamol is considered a first-line treatment in the pharmacological therapy of pain and is positioned at the first step in the WHO scale of chronic pain treatment.
Mechanism of action
Paracetamol has a low affinity for cyclooxygenases 1 and 2 (COX-1 and COX-2) and underlies a very weak anti-inflammatory activity. It is thought (Graham GG, Scott KF 2005) that the anti-inflammatory action is attributable to weak inhibition of the prostaglandin synthesis pathway. In vivo, i.e. when the concentration of arachidonic acid is low (< 5 µmol/L), prostaglandin production is mostly determined by COX-1 and to a lesser extent by COX-2. Under physiological conditions and at therapeutic doses of acetaminophen, its weak inhibitory action on COX-1, which catalyzes the predominant low-rate biosynthesis, thus becomes significant and produces the mild inflammation-reducing effects observed in vivo.
Outside of COX-1 inhibition, it appears that there is a third brain-expressed cyclo-oxygenase isoform (COX-3) that may be the preferred target of acetaminophen and other antipyretics. Inhibition of this enzyme, which has been shown to be a molecular variant of COX-1, could account for some of the central analgesic and antifebrile effects mediated by paracetamol in humans, since they do not appear to be important in the rat.
Instead, the analgesic action is due to the metabolite AM404.
Paracetamol poisoning is a form of pharmaceutical poisoning obtained by high administration of the analgesic drug paracetamol. Paracetamol poisoning causes liver damage and is one of the most common causes of poisoning in the world. In the United States of America and the United Kingdom, it is the most common cause of fulminant liver failure.
Many individuals with acetaminophen poisoning may not develop any symptoms in the first 24 hours following the overdose. Others may initially report nonspecific symptoms such as vague abdominal pain and nausea. As the poisoning progresses, signs of liver failure may develop, including hypoglycemia, metabolic acidosis, hemorrhagic diathesis, and hepatic encephalopathy. Spontaneous resolution of symptoms may occur in some patients although untreated cases may also lead to death.
Liver damage, or hepatotoxicity, does not result from acetaminophen as such, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI reduces the concentration of glutathione, a natural antioxidant, in the liver and causes direct damage to liver cells leading to liver failure. Risk factors for toxicity include chronic excessive alcohol intake, fasting or anorexia nervosa, and the use of certain medications such as isoniazid.
The goal of treatment is to remove acetaminophen from the body and restore glutathione. Activated charcoal may be used to reduce the absorption of paracetamol, if this has not yet occurred completely or if the patient presents for treatment immediately after overdose. The antidote acetylcysteine, on the other hand, acts as a precursor of glutathione, helping the body to regenerate enough of it to prevent liver damage. Liver transplantation may be necessary if severe liver damage occurs. On average, patients treated early have a good prognosis while patients who develop severe liver damage generally have a poor prognosis. Efforts to prevent acetaminophen overdose include limiting sales per person and combining acetaminophen with methionine, which is converted to glutathione in the liver.
Signs and symptoms
The symptomatology of paracetamol poisoning develops in three phases. The first phase begins within a few hours of the overdose, and consists of nausea, vomiting, pallor and sweating. In any case, patients often have no specific symptoms or only mild symptoms in the first 24 hours following poisoning. Rarely, following severe overdoses, patients may develop symptoms of metabolic acidosis and coma early in the course of the poisoning.
The second phase occurs between 24 hours and 72 hours following overdose and consists of signs of increasing liver damage. In general, damage occurs in liver cells (hepatocytes) as they metabolize the paracetamol. The individual may experience right upper quadrant abdominal pain. The increasing liver damage also changes biochemical markers of liver function; International normalized ratio (INR) and the liver transaminases ALT and AST rise to abnormal levels. Acute kidney failure may also occur during this phase, typically caused by either hepatorenal syndrome or multiple organ dysfunction syndrome. In some cases, acute kidney failure may be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced in greater quantities in the kidney than in the liver.
The third phase follows at 3 to 5 days, and is marked by complications of massive liver necrosis leading to fulminant liver failure with complications of coagulation defects, low blood sugar, kidney failure, hepatic encephalopathy, hypoglycemia, brain swelling, sepsis, multiple organ failure, and death. If the patient survives the third stage, liver necrosis regresses and renal and liver function return to normal levels in a few weeks. The severity of paracetamol toxicity varies depending on the dose and whether appropriate treatment is received.