Paracetamol

 
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More about Paracetamol

What is/are Paracetamol?

Paracetamol INN (/ˌpærəˈsiːtəmɒl/ or /ˌpærəˈsɛtəmɒl/), or acetaminophen USAN Listeni/əˌsiːtəˈmɪnəfɨn/, chemically named N-acetyl-p-aminophenol, is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer).

Paracetamol is classified as a mild analgesic. It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post-surgical pain and providing palliative care in advanced cancer patients. Though acetaminophen is used to treat inflammatory pain, it is not generally classified as an NSAID because it exhibits only weak anti-inflammatory activity.

The onset of analgesia is approximately 11-29.5 minutes after oral administration of paracetamol, and its half-life is 1–4 hours. While generally safe for use at recommended doses (1,000 mg per single dose and up to 4,000 mg per day for adults), acute overdoses of paracetamol can cause potentially fatal kidney, brain and liver damage and, in rare individuals, a normal dose can do the same. The risk may be heightened by chronic alcohol abuse. Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand.

It is the active metabolite of the coal tar–derived phenacetin, once popular as an analgesic and antipyretic in its own right. However, unlike phenacetin and its combinations, paracetamol is not considered carcinogenic at therapeutic doses. The words acetaminophen (used in the United States, Canada, Japan, South Korea, Hong Kong, and Iran) and paracetamol (used elsewhere) both come from a chemical name for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for acetyl-para-aminophenol.

Medical uses

Fever

Paracetamol is approved for reducing fever in people of all ages. The World Health Organization (WHO) recommends that paracetamol only be used to treat fever in children if their temperature is greater than 38.5 °C (101.3 °F). The efficacy of paracetamol by itself in children with fevers has been questioned and a meta-analysis showed that it is less effective than ibuprofen.

Pain

Paracetamol is used for the relief of pains associated with many parts of the body. It has analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin in patients in whom excessive gastric acid secretion or prolongation of bleeding time may be a concern. Available without a prescription, it has in recent[when?] years increasingly become a common household drug.

Paracetamol can relieve pain in mild arthritis[citation needed] but has no effect on the underlying inflammation, redness, and swelling of the joint. It is as effective as the non-steroidal anti-inflammatory drug (NSAID) ibuprofen in relieving the pain of osteoarthritis of the knee.

Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the NSAIDs aspirin and ibuprofen. But research studies analysis showed that ibuprofen and paracetamol have similar effects in the treatment of headache.

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.

The efficacy of paracetamol when used in a combination form with weak opioids (such as codeine) has been questioned by recent[when?] data studies; the small amount of data available have made reaching a conclusion difficult. Combination drugs of paracetamol and strong opioids like morphine have been shown[by whom?] to reduce the amount of opioid used and improve analgesic effect as well as discouraging overuse of addictive opioids due to APAP's toxic effects, as it depletes glutathione and thus exacerbates disease in general.

A randomized controlled trial of acute musculoskeletal pain in children found that the standard over-the-counter dose of ibuprofen gives greater pain relief than the standard dose of paracetamol.

Psychological effects

Paracetamol acts on, and suppresses pain through, the central nervous system rather than the peripheral nervous system. Recent research suggests that it deadens the neural response that causes the pain of social rejection as well as neural responses related to physical pain.

Adverse effects

Paracetamol is metabolized by the liver and is hepatotoxic; side effects are multiplied when combined with alcoholic drinks, and very likely in chronic alcoholics or patients with liver damage. Prolonged daily use increases the risk of upper gastrointestinal complications such as stomach bleeding, and may cause kidney or liver damage. And chronic users of paracetamol may have a higher risk of developing blood cancer. However in recommended doses and for a limited course of treatment, the side effects of paracetamol are mild to non-existent.

In contrast to aspirin, paracetamol is not an antithrombotic, and thus may be used in patients where coagulation is a concern, and it does not cause gastric irritation. However, paracetamol does not help reduce inflammation, while aspirin does. Compared to ibuprofen—whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects.

Until 2010, paracetamol was believed safe in pregnancy (as it does not affect the closure of the fetal ductus arteriosus as NSAIDs can). However, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn. Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses. In one study, paracetamol use for fever in the first year of life was associated with a moderate increase in the incidence of asthmatic symptoms at 6–7 years, and that paracetamol use, both in the first year of life and in children aged 6–7 years, was associated with a moderate increased incidence of rhinoconjunctivitis and eczema.

Overdose

Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts. People who take overdoses of paracetamol do not lose consciousness, although most people who use paracetamol wrongly believe that they will be rendered unconscious by the drug. The process of dying from an overdose usually takes three to five days.

Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom. Toxicity of paracetamol arises often due to its quinone metabolite. Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.

Untreated overdose can lead to liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione.[40] Activated charcoal can be used to decrease absorption of paracetamol if the patient presents for treatment soon after the overdose. While the antidote, acetylcysteine, (also called N-acetylcysteine or NAC) acts as a precursor for glutathione, helping the body regenerate enough to prevent damage to the liver, a liver transplant is often required if damage to the liver becomes severe. N-Acetylcysteine also helps in neutralizing the imidoquinone metabolite of acetaminophen. Renal failure is also a possible side effect.

There are tablets available (brand-name in the UK Paradote) that combine paracetamol with an antidote (methionine), to protect the liver in case of an overdose.

In June 2009, a U.S. Food and Drug Administration (FDA) advisory committee recommended that new restrictions should be placed on paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage at any given time would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics would be prohibited. Committee members were particularly concerned by the fact that the present maximum dosages of paracetamol had been shown to produce alterations in hepatic function. In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit the amount of paracetamol to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk for severe liver damage. Manufacturers will have three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit. In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.

Mechanism of action

To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2. While it has analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is the high level of peroxides present in inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to NSAIDs can be observed. An article in Nature Communications from researchers in London, UK and Lund, Sweden in November 2011 has found a hint to the analgesic mechanism of paracetamol (acetaminophen), being that the metabolites of paracetamol e.g. NAPQI, act on TRPA1-receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain. This conclusion has been contested in a new hypothesis paper on how paracetamol might act. The author concedes that NAPQI is the active metabolite but that this reactive compound should react not only with the thiol in TRPA1 but also with any other suitably available nucleophile that it happens to encounter. It is suggested that thiol groups in cysteine proteases, e.g. the proteases that take part in the processing of procytokines, such as those generating IL-1β and IL-6, might be the targets giving rise to overall analgesic effects. Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes.

The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule that is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step. Only when appropriately oxidized is the COX enzyme highly active. Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.This leads to a reduced amount of prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.

Paracetamol also modulates the endogenous cannabinoid system. Paracetamol is metabolized to AM404, a compound with several actions; what is most important is that it inhibits the reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide reuptake would result in lower synaptic levels and less activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). By inhibiting anandamide reuptake, levels in the synapse remain high and are able to desensitize the TRPV1 receptor much like capsaicin. Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine. Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves the endogenous cannabinoid system. Spinal TRPA1 receptors have also been demonstrated to mediate antinociceptive effects of paracetamol and Δ9-tetrahydrocannabinol in mice. Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes and, because paracetamol's action is partially similar to aspirin's, much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.

The exact mechanisms by which COX is inhibited in various circumstances are still a subject of discussion. Because of differences in the activity of paracetamol, aspirin, and other NSAIDs, it has been postulated that further COX variants may exist. One theory holds that paracetamol works by inhibiting the COX-3 isoform - a COX-1 splice variant - of the COX family of enzymes. When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol. However, some research has suggested that, in humans and mice, the COX-3 enzyme is without inflammatory action and paracetamol's blockage of it is not significant in its functioning in humans. Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that, in an inflammatory environment where the concentration of peroxides is high, the high oxidation state of paracetamol prevents its actions. This idea would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc. The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.

Paracetamol's increase of social behavior in mice (which corresponds to its reduction of social rejection response in humans) does not appear to be due to cannabinoid receptor type 1 activity. It may result from serotonin receptor agonism.

This article uses material from the Wikipedia article Paracetamol, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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