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Acetaminophen

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~~Acetaminophen belongs to a class of drugs called analgesics (pain relievers) and antipyretics (~~<~~font color="#000000">fever</font~~p> ~~reducers). The exact mechanism of action of acetaminophen is not known.~~ Acetaminophen relieves pain by elevating the pain threshold, that is, by requiring a greater amount of pain to develop before a person feels it. It reduces fever through its action on the heat-regulating center of the brain. Specifically, it tells the center to lower the body's temperature when the temperature is elevated. The FDA approved acetaminophen in 1951.or ~~ ~~ Paracetamol (INN) (IPA: /ˌpærəˈsiːtəmɒl, -ˈsɛtə-/) or acetaminophen (USAN) paracetamol is a widely-used analgesic and antipyretic. Derived from coal tar, it is the active metabolite of phenacetin, but unlike phenacetin, ~~paracetamol~~ acetaminophen has not been shown to be carcinogenic in any way. Unlike aspirin, it is not a very effective anti-inflammatory agent. It is well tolerated, lacks many of the side-effects of aspirin, and is available over-the-counter, so it is commonly used for the relief of fever, headaches, and other minor aches and pains. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) to be used, thereby minimizing overall side-effects. It is also used in combination with opioid analgesics.[1] It is a major ingredient in numerous cold and flu medications, including Tylenol and Panadol, among others. It is considered safe for human use at recommended doses; however, acute overdose can cause fatal liver damage often heightened with use of alcohol, and the number of accidental self-poisonings and suicides has grown in recent years[citation needed].

The words acetaminophen and paracetamol come from the chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. (The brand name Tylenol also derives from this name: para-acetylaminophenol.) In some contexts, it is shortened to APAP, for N-acetyl-para-aminophenol.

~~<table id="toc" summary="Contents" class="toc">~~ ~~<tbody>~~ ~~<tr>~~ ~~<td>~~ ~~<div id="toctitle">~~ ~~<h2>Contents</h2>~~ ~~[hide]</div>~~ ~~<ul>~~ ~~<li class="toclevel-1">1 History </li>~~ ~~<li class="toclevel-1">2 Chemistry~~ ~~<ul>~~ ~~<li class="toclevel-2">2.1 Structure and reactivity </li>~~ ~~<li class="toclevel-2">2.2 Synthesis </li>~~ ~~</ul>~~ ~~</li>~~ ~~<li class="toclevel-1">3 Available forms </li>~~ ~~<li class="toclevel-1">4 Mechanism of action </li>~~ ~~<li class="toclevel-1">5 Metabolism </li>~~ ~~<li class="toclevel-1">6 Comparison with NSAIDs~~ ~~<ul>~~ ~~<li class="toclevel-2">6.1 Efficacy </li>~~ ~~<li class="toclevel-2">6.2 Adverse effects </li>~~ ~~</ul>~~ ~~</li>~~ ~~<li class="toclevel-1">7 Toxicity~~ ~~<ul>~~ ~~<li class="toclevel-2">7.1 Mechanism </li>~~ ~~<li class="toclevel-2">7.2 Toxic dose </li>~~ ~~<li class="toclevel-2">7.3 Risk factors </li>~~ ~~<li class="toclevel-2">7.4 Natural history </li>~~ ~~<li class="toclevel-2">7.5 Diagnosis </li>~~ ~~<li class="toclevel-2">7.6 Treatment~~ ~~<ul>~~ ~~<li class="toclevel-3">7.6.1 Initial measures </li>~~ ~~<li class="toclevel-3">7.6.2 Acetylcysteine </li>~~ ~~</ul>~~ ~~</li>~~ ~~<li class="toclevel-2">7.7 Prognosis </li>~~ ~~<li class="toclevel-2">7.8 Prevention </li>~~ ~~</ul>~~ ~~</li>~~ ~~<li class="toclevel-1">8 Effects on animals </li>~~ ~~<li class="toclevel-1">9 See also </li>~~ ~~<li class="toclevel-1">10 Notes and references </li>~~ ~~<li class="toclevel-1">11 External links </li>~~ ~~</ul>~~ ~~</td>~~ ~~</tr>~~ ~~</tbody></table>~~<script type="text/javascript">

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<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">History</h2p>

In ancient and medieval times, known antipyretic agents were compounds contained in white willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds contained in cinchona bark.[2] Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned the work after deciding it was impractical).[3]

When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878;[4] however, paracetamol was not used in medical treatment for another 15 years. In 1893, paracetamol was discovered in the urine of individuals that had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time.

The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles."

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Chemistry</h2p>

<h3~~>[edit]</span~~> Structure and reactivity</h3>

Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.

<h3~~>[edit]</span~~> Synthesis</h3>

From the starting material phenol, paracetamol can be made in the following manner:

<ol>

Notice that the synthesis of paracetamol lacks one very significant difficulty inherent in almost all drug syntheses: Lack of stereocenters means there is no need to design a stereo-selective synthesis. More efficient, industrial syntheses are also available.

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Available forms</h2p>

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Mechanism of action</h2p>

The mechanism by which paracetamol reduces fever and pain is still a source of debate.[8] The reason for this confusion has largely been due to the fact that paracetamol reduces the production of prostaglandins—pro-inflammatory chemicals. Aspirin also inhibits the production of prostaglandins, but, unlike aspirin, paracetamol does not have much anti-inflammatory action. Likewise, whereas aspirin inhibits the production of the pro-clotting chemicals thromboxanes, paracetamol does not. Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and, because of paracetamol's partial similarity of aspirin's action, much research has focused on whether paracetamol also inhibits COX. It is now clear, however, that paracetamol acts via (at least) two pathways.[9][10][11][12]

The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule, which is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories, such as the NSAIDs, block this step. The activity of the COX enzyme relies on its being in the oxidized form to be specific, tyrosine 385 must be oxidized to a radical.[13][14] It has been shown that paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.[10][15]

A theory that held some sway, but has now largely been discarded, is that paracetamol inhibits the COX-3 isoform of the cyclooxygenase family of enzymes.[9][19] This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol. However, in humans and mice, the COX-3 enzyme is without inflammatory action, and is not modulated by paracetamol.[9]

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Metabolism</h2p>

At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione or administration of a sulfhydryl compound such as N-acetylcysteine, to produce a non-toxic conjugate that is eventually excreted by the kidneys.[20] Also, methionine has been recommended in some cases,[24] although recent studies show that N-acetylcysteine is a more effective antidote to paracetamol overdose.[25]

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Comparison with NSAIDs</h2p>

Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory activity, and so it is not considered to be a non-steroidal anti-inflammatory drug (NSAID).

<h3p> [edit]</span~~> <~~span class~~font size="~~mw-headline4">Efficacy</h3p>

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.[26] However, a randomized controlled trial of acute musculoskeletal pain in children found that the standard OTC dose of ibuprofen (400 mg) gives greater relief of pain than the standard dose of paracetamol (1000  mg).[27]

<h3~~>[edit]</span~~> Adverse effects</h3>

In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation as much as NSAIDs, or affect function of the kidneys. However, some studies have shown that high dose-usage (greater than 2000 mg per day) does increase the risk of upper gastrointestinal complications.[28]

Paracetamol is safe in pregnancy, and does not affect the closure of the fetal ductus arteriosus as NSAIDs can. Unlike aspirin, it is safe in children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses.

Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to cause rebound headache (medication overuse headache), although less of a risk than ergotamine or triptans used for migraines.[29]

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Toxicity</h2p>

Paracetamol is contained in many preparations (both over-the-counter and prescription-only medications). In some animals—for example, cats—small doses are toxic. Because of the wide availability of paracetamol, there is a large potential for overdose and toxicity.[30] Without timely treatment, overdose can lead to liver failure and death within days; paracetamol toxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.[31][32] It is sometimes used in suicide attempts by those unaware of the prolonged timecourse and high morbidity (likelihood of significant illness) associated with paracetamol-induced toxicity in survivors.

In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in non-pharmacy outlets.[33] Up to 100 tablets may be sold in a single transaction, however in pharmacies, 32 may only be sold, with more being sold at a pharmacists discretion. In Ireland, the limits are 24 and 12 tablets, respectively. In Australia, paracetamol tablets are available at supermarkets in small-pack sizes, whereas, with children's formulations, pack sizes greater than 48 tablets and suppositories are restricted to pharmacies.

<h3~~>[edit]</span~~> Mechanism</h3>

Paracetamol is mostly converted to inactive compounds via Phase II metabolism by conjugation with sulfate and glucuronide, with a small portion being oxidized via the cytochrome P450 enzyme system. Cytochromes P450 2E1 (CYP2E1) and 3A4 (CYP3A4) convert paracetamol to a highly-reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI).[34][35][36]

Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs.[34]

<h3~~>[edit]</span~~> Toxic dose</h3>

The toxic dose of paracetamol is highly variable. In individuals over 6 years of age, single doses above 200 mg/kg consumed over a single 24-hour period have a reasonable likelihood of causing toxicity. If an individual has consumed large quantities of paracetamol over a 48 hour period, a dose of above 6 grams or 150 mg/kg in the subsequent 24 hour period may cause toxicity.[37] Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of doses as low as 4 g/day, and death with as little as 6 g/day. Consumption of alcohol has been tied to a smaller dose toxicity.

In children of 6 and under, acute doses above 10 grams or 200 mg/kg could potentially cause toxicity. This higher threshold is largely due to larger kidneys and livers relative to body size in children versus adults, and hence greater tolerance per body mass of paracetamol overdose than adults.[38] Acute paracetamol overdose in children rarely causes illness or death with chronic, supratherapeutic doses being the major cause of toxicity in children.

Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol when checking a person's dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication, and sometimes in combination with opioids such as hydrocodone to deter people from using it recreationally or becoming addicted to the opioid substance. In fact, the human toll of paracetamol, in terms of both fatal overdoses and chronic liver toxicity, likely far exceeds the damage caused by the opioids themselves.[41][page # needed]

<h3~~>[edit]</span~~> Risk factors</h3>

Chronic excessive alcohol consumption can induce CYP2E1, thus increasing the potential toxicity of paracetamol.[42] For this reason, analgesics such as aspirin or ibuprofen are often recommended over paracetamol for relief of hangovers when other factors, such as gastric irritation, are not involved.

Fasting is a risk factor, possibly because of depletion of hepatic glutathione reserves.

It is well documented that concomitant use of the CYP2E1 inducer isoniazid increases the risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear.[43][44] Concomitant use of other drugs that induce CYP enzymes such as antiepileptics (including carbamazepine, phenytoin, and barbiturates) have also been reported as risk factors.

<h3~~>[edit]</span~~> Natural history</h3>

Individuals that have overdosed on paracetamol, in general, have no specific symptoms for the first 24 hours. Although nausea, vomiting, and diaphoresis may occur initially, these symptoms, in general, resolve after several hours. After resolution of these symptoms, individuals tend to feel better, and may believe that the worst is over. If a toxic dose was absorbed, after this brief feeling of relative wellness, the individual develops overt liver failure. In massive overdoses, coma and metabolic acidosis may occur prior to hepatic failure.

In general, damage occurs in hepatocytes as they metabolize the paracetamol. Rarely, acute renal failure also may occur. This is usually caused by either hepatorenal syndrome or Multiple organ dysfunction syndrome. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced more in the kidneys than in the liver.[45]

The prognosis of paracetamol toxicity varies depending on the dose and the appropriate treatment. In some cases, massive hepatic necrosis leads to fulminant hepatic failure with complications of bleeding, hypoglycemia, renal failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course, hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks.

<h3~~>[edit]</span~~> Diagnosis</h3>

Evidence of liver toxicity may develop in one to four days, although, in severe cases, it may be evident in 12 hours. Right-upper-quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times (in particular, elevated prothrombin time). After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000 IU/L. In general, the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity.

A drug nomogram was developed in 1975, which estimated the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion.[46] To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended, since the history in these cases is often poor and a toxic level at any time is a reason to give the antidote.

<h3p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Treatment</h3p>

<h4~~>[edit]</span~~> Initial measures</h4>

The initial treatment for uncomplicated paracetamol overdose, similar to most other overdoses, is gastrointestinal decontamination. In addition, the antidote, acetylcysteine plays an important role. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this time. Absorption may be somewhat slowed when it is ingested with food. There is considerable room for physician judgement regarding gastrointestinal decontamination; activated carbon administration is the most commonly-used procedure; however, gastric lavage may also be considered if the amount ingested is potentially life threatening and the procedure can be performed within 60 minutes of ingestion.[47] Syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated carbon and oral acetylcysteine.

Activated carbon adsorbs paracetamol, reducing its gastrointestinal absorption. Administering activated carbon also poses less risk of aspiration than gastric lavage. Previous to this method, there was reluctance to give activated carbon in paracetamol overdose, because of concern that it may also absorb acetylcysteine. Studies have shown that no more than 39% of an oral acetylcysteine is absorbed when they are administered together.[48] Other studies have shown that activated carbon seems to be beneficial to the clinical outcome. It appears that the most benefit from activated carbon is gained if it is given within two hours of ingestion.[49] However, administering activated carbon later than this can be considered in patients that may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained- or delayed-release paracetamol preparations. Activated carbon should also be administered if co-ingested drugs warrant decontamination. There are conflicting recommendations[48][50] regarding whether to change the dosing of oral acetylcysteine after the administration of activated carbon, and even whether the dosing of acetylcysteine needs to be altered at all.

<h4~~>[edit]</span~~> Acetylcysteine</h4>

Acetylcysteine (also called N-Acetylcysteine or NAC) works to reduce paracetamol toxicity by supplying sulfhydryl groups (mainly in the form of glutathione, of which it is a precursor) to react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. (NAC can be bought as a dietary supplement in the United States.)

If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity. If NAC is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute hepatic necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion.[51] In clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated carbon is probably not useful, and acetylcysteine is started immediately. In earlier presentations, the doctor can give carbon as soon as the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory.

Baseline laboratory studies include bilirubin, AST, ALT, and prothrombin time (with INR). Studies are repeated at least daily. Once it has been determined that a potentially-toxic overdose has occurred, acetylcysteine is continued for the entire regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard doses until hepatic function improves or until the patient has a liver transplant.

<h3~~>[edit]</span~~> Prognosis</h3>

The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Patients with a poor prognosis are usually identified for likely liver transplantation. Acidemia is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH less than 7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse hepatic encephalopathy, a markedly elevated prothrombin time, or a rise in prothrombin time from day three to day four. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).[53]

<h3~~>[edit]</span~~> Prevention</h3>

Besides preventing an overdose, one way to prevent liver damage may be the use of Paradote. Paradote is a combination tablet containing 100 mg methionine and 500 mg paracetamol. Methionine is included in order to ensure that sufficient levels of glutathione in the liver are maintained in order to minimize the liver damage caused if a paracetamol overdose is taken.

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Effects on animals</h2p>

Paracetamol is extremely toxic to cats, and should not be given to them under any circumstances. Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down and minute portions of a normal tablet for humans may prove fatal.[54] Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. After around two days, liver damage is evident, typically giving rise to jaundice. Unlike an overdose in humans, it is rarely liver damage that is the cause of death, instead methaemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation. Effective treatment is occasionally possible for small doses, but must be extremely rapid.

In dogs, paracetamol is a useful anti-inflammatory with a good safety record, causing a lower incidence of gastric ulceration than NSAIDs. It should be administered only on veterinary advice. A paracetamol-codeine product (trade name Pardale-V)[55] licensed for use in dogs is available on veterinary prescription in the UK.[56]

Paracetamol is lethal to snakes, also, and has been used in attempts to control the brown tree snake (Boiga irregularis) in Guam.[59]

<ul>

<li>Tylenol scare </li>

</ul>

<h2p>[edit]</span~~> <~~span class~~font size="~~mw-headline5">Notes and references</h2p>

</ol>

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~~<a id="External_links" name="External_links"></a>~~ <h2p>External links</h2p>

<ul>

<li><a class="external text" title="https://online.epocrates.com/u/10a307/acetaminophen?mode=SingleMatch&src=PK" rel="nofollow" href="https://online.epocrates.com/u/10a307/acetaminophen?mode=SingleMatch&src=PK">Acetaminophen on Epocrates Drug Lookup</a> </li>

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