Paracetamol , also known as acetaminophen or APAP , is a drug used to treat pain and fever. This is usually used to relieve mild to moderate pain. The evidence for its use to alleviate fever in children varies. It is often sold in combination with other drugs, as in many cold medicines. In combination with opioid pain medication, paracetamol is also used for severe pain such as cancer pain and pain after surgery. It is usually used either by mouth or rectal but is also available intravenously. The effects persist between two and four hours.
Paracetamol is generally safe at recommended doses. A serious skin rash may be rare, and too high a dose can cause liver failure. It seems safe during pregnancy and while breastfeeding. In those with liver disease, it may still be used, but in lower doses. Paracetamol is classified as a mild analgesic. It has no significant anti-inflammatory activity and the way it works is not entirely clear.
Paracetamol was discovered in 1877. It is the most commonly used drug for pain and fever both in the United States and Europe. It's in the List of Essential Medicines of the World Health Organization, the most effective and safe drugs needed in the health system. Paracetamol is available as a generic drug with trade names including Tylenol and Panadol among others. Wholesale prices in developing countries are less than 0.01 USD per dose. In the United States it costs about 0.04 USD per dose.
Video Paracetamol
Medical use
Fever
Paracetamol is used to reduce fever in people of all ages. The World Health Organization (WHO) recommends that paracetamol be used to treat fever in children only if their temperature is higher than 38.5 ° C (101.3 ° F). The efficacy of paracetamol by itself in children with fever has been questioned and meta-analysis shows that it is less effective than ibuprofen. Paracetamol has no significant anti-inflammatory effect.
Pain
Paracetamol is used to relieve mild to moderate pain. The use of intravenous forms of paracetamol for short-term pain in people in the emergency department is supported by limited evidence.
Osteoarthritis
The American College of Rheumatology recommends paracetamol as one of several treatment options for people with hip, hand or knee arthritis pain that does not improve with exercise and weight loss. However, the 2015 review found that it provides little benefit to osteoarthritis.
Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as aspirin NSAIDs and ibuprofen, but ibuprofen and paracetamol have the same effect in the treatment of headache. Paracetamol can relieve pain in mild arthritis, but it has no effect on underlying inflammation, redness, and swelling of the joints. It has analgesic properties that are comparable to aspirin, while its anti-inflammatory effect is weaker. Better tolerated than aspirin because of concerns about bleeding with aspirin.
Lower back pain
Based on systematic reviews, paracetamol is recommended by the American College of Physicians and the American Pain Society as first-line treatment for low back pain. In contrast, other systematic reviews have concluded that evidence of its efficacy is lacking.
Headache
A joint statement from Germany, Austria, and Swiss headache and the German Neurological Society recommends the use of paracetamol in combination with caffeine as one of the first-line treatments for the treatment of tension or migraine headaches. In the treatment of acute migraine, it was superior to placebo, with 39% of people experiencing pain relief in one hour compared with 20% in the control group.
Postoperative pain
Paracetamol in combination with NSAIDs may be more effective for treating postoperative pain than paracetamol alone or NSAID alone.
Dental use
NSAIDs such as ibuprofen, naproxen, diclofenac are more effective than paracetamol to control dental pain or pain arising from dental procedures; the combination of NSAIDs and paracetamol is more effective than alone. Paracetamol is particularly useful when NSAIDs are contraindicated due to hypersensitivity or a history of gastrointestinal ulceration or bleeding. It can also be used in combination with NSAIDs when it is not effective in controlling dental pain alone. Preoperative Cochrane analgesic reviews for additional pain relief in children and adolescents showed no evidence of benefit in taking paracetamol before dental treatment to help reduce pain after treatment for procedures under local anesthesia, but low evidence quality.
More
The efficacy of paracetamol when used in combination with weak opioids (such as codeine) increases for about 50% of people but with an increase in the number of adverse events. The combination of powerful paracetamol and opioid drugs such as morphine increases the analgesic effect.
The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of generalized pain conditions including toothache, postpartum pain, and headache.
Patent ductus arteriosus
Paracetamol is used to treat patent ductus arteriosus, a condition that affects the newborn when the blood vessels used in developing the lungs fail to close as usual, but evidence for the safety and efficacy of paracetamol for this purpose is lacking. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin and ibuprofen, have also been used but the evidence for them is also not strong. This condition appears to be caused in part by an overactive prostaglandin E2 (PGE 2 ), signifying primarily through the EP receptor 4 but possibly also via EP2 and EP3 receptors.
Maps Paracetamol
Adverse effects
Healthy adults who consume regular doses up to 4,000 mg daily show little evidence of toxicity (although some researchers disagree). They are more likely to have abnormal liver function tests, but this significance is uncertain.
Liver damage
Acute paracetamol overdose can cause fatal liver damage. In 2011, the US Food and Drug Administration launched a public education program to help consumers avoid overdoses, warning: "Acetaminophen can cause serious liver damage if more than directed use." In the 2011 Safety Warning, the FDA immediately asked manufacturers to update the label of all presetaminophen products prescribed to warn of potential risks for severe liver injury and requires that the combination contain no more than 325 mg of acetaminophen. Overdose is often associated with the use of high-dose prescription opioids, since these opioids are most often combined with acetaminophen. The risk of overdose may increase with frequent alcohol consumption.
The toxicity of paracetamol is the leading cause of acute liver failure in the Western world and accounts for most drug overdose in the United States, Britain, Australia and New Zealand. According to the FDA, in the United States there are "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year associated with associated acetaminophen overdose during the 1990s.In this estimate, overdose of acetaminophen inadvertently accounts for nearly 25% of emergencies. department visits, 10% of hospitalization, and 25% of deaths. "
Paracetamol is metabolized by the liver and is hepatotoxic; side effects multiplied when combined with alcoholic beverages, and very likely in chronic alcoholics or people with liver damage. Several studies have demonstrated the possibility of an increased risk of upper gastrointestinal complications such as abdominal bleeding when high doses are taken chronically. Kidney damage is seen in rare cases, most commonly in overdose.
Skin reactions
On August 2, 2013, the US Food and Drug Administration (FDA) issued a new warning about paracetamol. This suggests that the drug may cause rare and possibly fatal skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Prescription power products will be required to carry warning labels about skin reactions, and the FDA has urged manufacturers to do the same with products sold freely.
Asthma
There is a connection between the use of paracetamol and asthma, but whether this causal relationship is still debated in 2017. Certain evidence suggests that this relationship tends to reflect confounding rather than completely causally. A review of 2014 found that among children, the association disappears when respiratory infections are taken into account.
In 2014, the American Academy of Pediatrics and the National Institute for Health and Nursing Excellence (NICE) continue to recommend paracetamol for pain and discomfort in children, but some experts have recommended that the use of paracetamol by children with asthma or at risk of asthma should be avoided.
Other factors
Unlike aspirin, paracetamol does not prevent blood from clotting (it is not antiplatelet), and thus can be used in people who have concerns with blood clotting. In addition it does not cause stomach irritation. However, paracetamol does not help reduce inflammation, while aspirin. Compared with ibuprofen - the side effects may include diarrhea, vomiting and abdominal pain - paracetamol has fewer adverse gastrointestinal effects. Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with the risk of Reye syndrome in children with viral illness. If taken recreationally with opioids, there is weak evidence suggesting that it may cause hearing loss.
Overdose
Overdose of untreated paracetamol results in a long and painful disease. Signs and symptoms of paracetamol toxicity may be initially absent or symptoms that are not specific. The first symptoms of overdose usually begin several hours after consumption, with nausea, vomiting, sweating, and pain when acute liver failure begins. People who take paracetamol overdose do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol incorrectly believe they will become unaware of the drug. Death due to overdose takes 3-5 days to 4-6 weeks.
Paracetamol hepatotoxicity is the most common cause of acute liver failure in the United States and the United Kingdom. Paracetamol overdose results in more calls to a poison control center in the US than an overdose of other pharmacological substances. The toxicity of paracetamol is believed to be caused by its quinone metabolite.
Untreated overdose can lead to liver failure and death within a few days. Treatment is intended to remove paracetamol from the body and fill glutathione. Activated charcoal can be used to reduce paracetamol absorption if the person comes to the hospital immediately after an overdose. While the antidote, acetylcysteine ​​(also called N-acetylcysteine ​​or NAC), acts as a precursor for glutathione, helps the body adequately regenerate to prevent or at least reduce the likelihood of damage to the liver, frequent liver transplantation necessary if the damage to the liver becomes severe. NAC is usually given after treatment dosage (one for people with risk factors, and one for those who do not) but the use of nomograms is no longer recommended as evidence to support the use of poor and inconsistent risk factors, and many of these risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. NAC also helps neutralize imidoquinone metabolites from paracetamol. Kidney failure is also a possible side effect.
Until 2004, tablets are available (brand name in UK Paradote) that combines paracetamol with an antidote (methionine) to protect the liver in case of overdose. One theoretical option, but rarely used in the United States is to ask mixed pharmaceuticals to make the same drug mixture for people at risk.
In June 2009, the US Food and Drug Advisory Committee (FDA) recommended that new restrictions be placed on the use of paracetamol in the United States to help protect people from potential toxic effects. The maximum dose at any given time will decrease from 1000 mg to 650 mg, while a combination of paracetamol and opioid analgesics will be prohibited. Committee members are very concerned about the fact that the current maximum dose of paracetamol has been shown to produce a change in liver function.
In January 2011, the FDA called on 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 combinations of paracetamol products to warn potential risks. severe liver damage. Manufacturers have three years to limit the amount of paracetamol in their prescription drug products to 325 mg per unit dose. In November 2011, the Regulatory Body of Drugs and Health Care Products revised the British dosage of liquid paracetamol for children.
Pregnancy
Experimental studies in animals and human cohort studies have shown no detectable improvement in congenital malformations associated with paracetamol use during pregnancy. In addition, paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can.
Maternal use of paracetamol during pregnancy is associated with an increased risk of asthma in children. It is also associated with an increase in ADHD but it is not clear whether the relationship is causal. The 2015 review suggests that paracetamol remains the first-line recommended drug for pain and fever during pregnancy, despite these concerns.
Cancer
Several studies have found an association between paracetamol and a slight increase in kidney cancer, but have no effect on the risk of bladder cancer.
Pharmacology
Action mechanism
The mechanism of action of paracetamol is not fully understood. Unlike NSAIDs such as aspirin, paracetamol does not seem to inhibit the function of cyclooxygenase (COX) enzymes outside the central nervous system, and this seems to be the reason why it is not useful as an anti-inflammatory. It appears to selectively inhibit the activity of COX in the brain, which may contribute to its ability to treat fever and pain. This activity does not seem to be a direct inhibition by blocking active sites, but by reducing COX, which must be oxidized to work.
It is also seen that paracetamol may modulate endogenous cannabinoid systems in the brain through the paracetamol metabolite, AM404. AM404 seems to inhibit the endogenous reuptake of cannabinoid/vanilloid anandamide by neurons, making it more available to relieve pain. AM404 also seems to be able to directly activate TRPV1 (the old name: vaniloid receptor), which also inhibits pain signals in the brain.
Pharmacokinetics
Once taken through the mouth it is rapidly absorbed by the gastrointestinal tract (GI) (although absorption through the stomach is negligible); its distribution volume is approximately 50 L. Serum concentrations after a typical paracetamol dose typically reach below 30 Âμg/ml (200 μmol/L). After four hours, the concentration is usually less than 10 Âμg/mL (66 Âμmol/L).
Paracetamol is metabolized primarily in the liver, into toxic and non-toxic products. Three important metabolic pathways:
- Glucuronidation (45-55%), by UGT1A1 and UGT1A6;
- Sulfation (sulphate conjugation) (20-30%) by SULT1A1;
- N -hydroxylation and dehydration, then conjugate glutathione, (less than 15%). The cytochrome P450 liver enzyme system of metabolises paracetamol (especially CYP2E1), forms a small but significant metabolite known as NAPQI ( N -acetyl- p -benzoquinone imine) (also known as N -acetylimidoquinone). NAPQI is then irreversibly conjugated with sulfhydryl groups of glutathione.
The three pathways produce end products that are inactive, non-toxic, and ultimately excreted by the kidneys. However, in the third line, the product between NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this is an example of poison. NAPQI production is mainly due to two cytochrome P450 isoenzymes: CYP2E1 and CYP3A4. In usual doses, NAPQI is rapidly detoxified by conjugation with glutathione.
Chemistry
Chemical Properties
Paracetamol consists of a benzene ring core, replaced by a hydroxyl group and a nitrogen atom of the amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). This is a broadly conjugated system, such as the free electron pair on hydroxyl oxygen, pi-benzene cloud, the nitrogen free electron pair, the p-orbitals on carbonyl carbon, and the free electron pairs on the carbonyl oxygen are all conjugated. The presence of two activation groups also makes the benzene ring highly reactive to electrophilic aromatic substitution. Because the substituents are ortho, the -directing and para to each other, all positions on the rings are more or less the same are activated. Conjugation also greatly reduces the alkalinity of oxygen and nitrogen, while making hydroxyl acids through the delocalization of charges developed in phenoxide anions.
Paracetamol is part of a class of drugs known as "aniline analgesics"; this is the only remedy still used today. It is not considered NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor). This is despite evidence that paracetamol and NSAIDs have similar pharmacological activity.
Synthesis
Original (Boots)
The original method for production involving nitration of phenol with sodium nitrate gives a mixture of two isomers, from which 4-nitrophenol desired (bp 279 ° C) can be easily separated by steam distillation. In this electrophilic aromatic substitution reaction, phenol oxygen is very active, so the reaction requires only mild conditions compared to the nitration of benzene itself. The nitro group is then reduced to amine, giving 4-aminophenol. Finally, the amine is acetylated with acetic anhydride. Direct industrial hydrogenation is used, but on a laboratory scale sodium borohydride is used.
Synthesis green (er)
An alternative industrial synthesis developed by Hoechst-Celanese involves the direct acylation of phenol with HF-catalyzed acetate anhydride, the conversion of ketone to ketoxime with hydroxylamine, followed by an acid catalyzed Beckmann rearrangement to provide an amide.
Direct synthesis
Recently (2014) the synthesis of "one pot" of hydroquinone was described before the Royal Society of Chemistry. The process can be summarized as follows:
- Hydroquinone, ammonium acetate and acetic acid are mixed in the argon atmosphere and heated slowly to 230 ° C. The mixture is stirred at this temperature for 15 hours. After cooling the acetic acid is evaporated and the precipitate filtered, washed with water and dried to give paracetamol as a white solid.
The authors proceeded to claim 88% yield and 99% purity.
Reactions
4 -Aminophenol can be obtained by hydrolysis of the amide of paracetamol. 4 -Aminophenol is prepared in this way, and related to commercially available Metol, has been used as a developer in photography by fans. This reaction is also used to determine the paracetamol in the urine sample: After hydrolysis with hydrochloric acid, 4 -aminofenol reacts in ammonia solution with phenol derivatives, eg. salicylic acid, to form an indophenol dye under oxidation by air.
History
Acetanilide was the first aniline derivative accidentally found to have analgesics and antipyretic properties, and was rapidly incorporated into medical practice under the name Antifebrin by A. Cahn and P. Hepp in 1886. But the unacceptable toxic effects, the most alarming creatures. cyanosis due to methemoglobinemia, were asked to look for less toxic aniline derivatives. Harmon Northrop Morse had synthesized paracetamol at Johns Hopkins University by reducing p -nitrophenol with lead in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol in humans.. In 1893, von Mering published a paper reporting the clinical results of paracetamol with phenacetin, another aniline derivative. Von Mering claims that, unlike phenacetin, paracetamol has little tendency to produce methemoglobinemia. Paracetamol is then quickly discarded in favor of phenacetin. The sale of phenacetin established Bayer as a leading pharmaceutical company. Partly overshadowed by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin has been popular for decades, especially in the widely-shared "headache mix", usually containing phenacetin, an aminopyrine derivative of aspirin, caffeine, sometimes a barbiturate.
Paracetamol is an active metabolite of phenacetin and acetanilide, both of which were once popular as analgesics and antipyretics in themselves. However, unlike phenacetin, acetanilide and their combination, paracetamol is not considered carcinogenic in therapeutic doses.
Von Mering's claim remains essentially unchallenged for half a century, until two research teams from the United States analyzed the metabolism of acetanilide and paracetamol. In 1947 David Lester and Leon Greenberg found strong evidence that paracetamol was the main metabolite of acetanilide in human blood, and in subsequent studies they reported that large doses of paracetamol administered to albino mice did not cause methemoglobinemia. In three papers published in the September 1948 issue of the Journal of Experimental Pharmacology and Therapy, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol is the main metabolite of acetanilide in human blood, that it is as effective as analgesics as its predecessor. They also suggest that methemoglobinemia is produced in humans primarily by other metabolites, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 determined that phenacetin was also metabolized to paracetamol. This causes "reinvention" of paracetamol. It has been suggested that contamination of paracetamol with 4-aminophenol, von mering substance from synthesized, may be the cause of false findings.
Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine. The 1951 report of three users who developed agranulocytosis blood disease caused their removal from the market, and it took several years until it became clear that the disease was unrelated. Paracetamol was marketed in 1953 by Sterling-Winthrop Co. as Panadol, is only available by prescription, and promoted as better for aspirin as it is safe for children and people with ulcers. In 1955, paracetamol was marketed as Tylenol Elixir Son by McNeil Laboratories. In 1956, 500 mg of paracetamol tablets went on sale in the UK under the trade name Panadol, produced by Frederick Stearns & amp; Co., a subsidiary of Sterling Drug Inc. In 1963, paracetamol was added to British Pharmacopoeia , and has gained popularity since then as an analgesic agent with few side effects and little interaction with other pharmaceutical agents. Concerns about the safety of paracetamol delayed its wide acceptance until the 1970s, but by 1980, paracetamol sales exceeded aspirin in many countries, including the UK. This is accompanied by the death of commercial phenacetin, which is blamed for the causes of analgesic nephropathy and haematological toxicity. In 1988 Sterling Winthrop was acquired by Eastman Kodak who sold a patent on dope to SmithKline Beecham in 1994.
Available without a recipe since 1959, has since become an ordinary household remedy. Patents on paracetamol have long been over, and generic versions of these drugs are widely available.
Society and culture
Naming
Acetaminophen is a name commonly used in the United States (USAN), Japan (JAN), Canada Venezuela, Colombia, and Iran; paracetamol is used in international places (INN, AAN, BAN). In some contexts, such as the prescription painkiller bottle that incorporates this drug, it is simply abbreviated as APAP, for a cetyl- p fig- a mino p henol.
Both acetaminophen and paracetamol are derived from the chemical name for the compound: para - acet yl aminophen ol and par a - acet yl am inophen ol .
Available form
Paracetamol is available in tablets, capsules, liquid suspensions, suppositories, intravenous, intramuscular, and effervescent forms.
In some formulations, paracetamol is combined with opioid codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the US, this combination is only available with a doctor's prescription, while the lowest power preparations are at counters in Canada, and in other countries other forces may be available at the counter. Paracetamol is also combined with other opioids such as dihydrocodeine, called co-dydramol (BAN), oxycodone or hydrocodone. Another commonly used analgesic combination is paracetamol in combination with propoxyphene napsylate. A combination of paracetamol, codeine and soothing doxylamine succinate are also available. The efficacy of a combination of paracetamol/codeine has been questioned by recent research.
Paracetamol is commonly used in multi-ingredient preparations for migraine headaches, usually including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.
Paracetamol is sometimes combined with phenylephrine hydrochloride. Sometimes a third active ingredient, such as ascorbic acid, caffeine, chlorpheniramine maleate, or guaifenesin is added to this combination.
When marketed in combination with diphenhydramine hydrochloride, it is often labeled "PM" and is intended as a sleep aid. Diphenhydramine hydrochloride is known to have hypnotic effects and non-custom formation. Unfortunately it has been involved in the development of restless leg syndrome occasionally.
Controversy
In September 2013, an episode of This American Life titled "Use Only as Directed" highlights the deaths from paracetamol overdose. This report was followed by two reports by ProPublica stating that "the FDA has long known research showing the risk of acetaminophen, as well as Tylenol maker McNeil Consumer Healthcare, division of Johnson & Johnson" and "McNeil, Tylenol maker,... have repeatedly opposed safety alerts, dosing restrictions and other measures intended to protect drug users. "
A report compiled by the FDA's internal working group illustrates the history of FDA initiatives designed to educate consumers about the risks of paracetamol overdose and notes that a challenge for the Agency has "identified the right message about the relative safety of acetaminophen, especially compared to other OTC pain relievers (eg aspirin and other NSAIDs) ". The report notes that "The chronic use of NSAIDs is also associated with significant morbidity and mortality • The NSAID's gastrointestinal risk is substantial, with mortality and hospitalization estimated in one publication as 3200 and 32,000 per year respectively • The likelihood of cardiovascular toxicity with the use of chronic NSAIDs has been became the main discussion recently, "eventually noting that" The goal of educational efforts is not to reduce the use of appropriate acetaminophen or encourage substitution for the use of NSAIDs, but rather to educate consumers so they can avoid unnecessary health risks. "
Veterinary use
Cat
Paracetamol is highly toxic to cats, which lack the necessary UGT1 enzymes to break it down safely. Early symptoms include vomiting, saliva, and tongue and gum changes.
Unlike an overdose in humans, liver damage is rarely the cause of death; on the contrary, the formation of methemoglobin and body production of Heinz in red blood cells inhibits oxygen transport by blood, causing shortness of breath (methemoglobemia and haemolytic anemia).
Treatment with N-acetylcysteine, methylene blue or both is sometimes effective after ingesting small doses of paracetamol.
Dog
Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported to be as effective as aspirin in treating musculoskeletal pain in dogs.
Paracetamol-codeine products (trade names Pardale-V) licensed for use in dogs are available for purchase under the supervision of a veterinarian, pharmacist or other qualified person. It should be given to the dog only with the advice of the veterinarian and with great care.
The main effect of dog toxicity is liver damage, and GI ulceration has been reported. N-acetylcysteine ​​therapy is efficacious in dogs when administered within two hours after paracetamol consumption.
Snake
Paracetamol is also deadly for snakes, and has been suggested as a chemical control program for invasive brown snake ( Boiga irregularis ) in Guam. An 80-mg dose is inserted into a dead rat propagated by a helicopter.
References
External links
- FDA: Safe Use of Pain Relieving Drug/Fever Reduction
- FDA: Consumer Updates "Acetaminophen and Liver Injury: Q and A for Consumers" (link)
- US. National Medical Library: Drug-Paracetamol Information Portal
Source of the article : Wikipedia
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