Paracetamol

Paracetamol (INN) (IPA: ) or acetaminophen (USAN) is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. Paracetamol is also useful in managing more severe pain, allowing lower dosages of additional NSAID or opioid analgesics to be used, so minimising overall side-effects. It is a major ingredient in numerous cold and flu medications and many prescription analgesics. It is remarkably safe in recommended doses, but because of its wide availability, deliberate or accidental overdoses are fairly common.

The words acetaminophen and paracetamol both come from the chemical names for the compound: N-acetyl-para-aminophenol and para-acetyl-amino-phenol. In some contexts, it is shortened to apap, for N-acetyl-para-amino-phenol.

History

In ancient and medieval times, the only antipyretic agents known 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. 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 Hoffman (this was also done by French chemist Charles Gergardt 40 years earlier, but he abandoned the work after deciding it was too impractable).^*

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. By this time, paracetamol had already been synthesized by Harmon Northrop Morse via the reduction of p-nitrophenol with tin in glacial acetic acid. While this was first performed in 1873, paracetamol was not used medically for another two decades. In 1893, paracetamol was discovered in the urine of individuals who 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.

In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a condition that decreases the oxygen-carrying capacity of blood and is potentially lethal. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol (acetaminophen), since it did not have the toxic effects of acetanilide.

The product went on sale in the United States in 1955 under the brand name Tylenol.

In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant. In June 1958 a children's formulation, Panadol Elixir, was released.

In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.

The U.S. patent on paracetamol has 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 are protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles."

Available forms

Panadol, which is marketed in Europe, Asia, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form or under a number of trade names: for instance Tylenol (McNeil-PPC, Inc), Anacin-3, Tempra and Datril. In some formulations paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4 and in the US is only available by prescription, while the lowest strength is over-the-counter in Canada. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol.

It is commonly administered in tablet, liquid suspension, suppository or intravenous form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4 grams. In recommended doses paracetamol is safe for children and infants as well as for adults.

The effectiveness of paracetamol is often underestimated because of its widespread availability.

Mechanism of action

Paracetamol has long been suspected of having a similar mechanism of action to aspirin because of the similarity in structure. That is, it has been assumed that paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX) enzyme.

However, there are important differences between the effects of aspirin and those of paracetamol. Prostaglandins participate in the inflammatory response, but paracetamol has no appreciable anti-inflammatory action. Furthermore, COX also produces thromboxanes, which aid in blood clotting — aspirin reduces blood clotting, but paracetamol does not. Finally, aspirin and the other NSAIDs commonly have detrimental effects on the stomach lining, where prostaglandins serve a protective role, but paracetamol is safe.

Indeed, while aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, paracetamol indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.

In 2002 it was reported that paracetamol selectively blocks a variant of the COX enzyme that was different from the then known variants COX-1 and COX-2. This enzyme, which is only expressed in the brain and the spinal cord, is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works.

A single study has shown that administration of paracetamol increases the bioavailability of serotonin (5-HT) in rats, but the mechanism is unknown and untested in humans.

Metabolism

Paracetamol is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion is metabolized via the hepatic cytochrome P450 enzyme system (specifically CYP2E1); the toxic effects of paracetamol are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine) that is produced through this enzyme, not paracetamol itself or any of the major metabolites. This toxic metabolite reacts with sulfhydryl groups. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.

Comparison with NSAIDs

Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties, and so it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation, or function of the kidneys.

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.

Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood in any way. Paracetamol and NSAIDs have the benefit of bearing a low risk of addiction, dependence, tolerance and withdrawal.

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.

Toxicity

Overview

Paracetamol has a narrow therapeutic index – the therapeutic dose is close to the toxic dose. Additionally, paracetamol is contained in many preparations (both over-the-counter and prescription only medications). This means that, despite being one of the safest analgesics available at recommended doses, there is a large potential for overdose and toxicity.

Single doses above 10 grams, chronic doses over 6 grams per day, or chronic doses over 4 grams per day in patients with conditions which may increase susceptibility to paracetamol toxicity (alcoholism, isoniazid use, prolonged fasting), can potentially cause major hepatotoxicity (damage to the liver). Without timely treatment, paracetamol overdose can lead to liver failure and death within days. Because of the wide over-the-counter availability of the drug, it is sometimes used in suicide attempts by those unaware of the prolonged timecourse and high morbidity associated with paracetamol-induced toxicity.

Mechanism of toxicity

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. Cytochrome P450 2E1 (CYP2E1) converts paracetamol to a highly reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI).

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, clinically leading to acute hepatic necrosis. In animal studies, 70% of hepatic glutathione must be depleted before hepatotoxicity occurs.

Risk factors for toxicity

The toxic dose of paracetamol is highly variable. In adults, single doses above 12 grams or 150 mg/kg have a reasonable likelihood of causing toxicity. In adults, single doses of more than 25 grams have a high risk of lethality. Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of smaller doses. However, acute paracetamol overdose in children rarely causes illness or death. This may be due in part to the immature cytochrome P450 (CYP) enzyme system in children. Chronic excessive ethanol (alcohol) consumption can induce CYP2E1, thus increasing the potential toxicity of paracetamol. For this reason, other analgesics such as aspirin or ibuprofen are sometimes recommended for hangovers.

Some individuals are more susceptible to hepatotoxicity, with toxic doses as low as 4 g/day, and death with as little as 6 g/day. 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 CYP2E1 induction is related to the hepatotoxicity in this case is unclear. Chronic alcoholism, which also induces CYP2E1, is also well known to increase the risk of paracetamol-induced hepatotoxicity. Concomitant use of other drugs which induce CYP enzymes such as antiepileptics (including carbamazepine, phenytoin, barbiturates, etc) have also been reported as risk factors.

Natural history

Individuals who have overdosed on paracetamol generally have no specific symptoms for the first 24 hours. Although nausea, vomiting, and diaphoresis are common initially, these symptoms resolve after several hours. After resolution of these non-specific 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 hepatic failure. In massive overdoses, coma and metabolic acidosis may occur prior to hepatic failure.

Damage generally occurs in hepatocytes as they metabolize the paracetamol. However, acute renal failure also may occur. This is usually caused by either hepatorenal syndrome or multi-system organ failure. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it is possible that the toxic metabolite is produced more in the kidneys than in the liver.

The prognosis of paracetamol 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.

Diagnosis

Evidence of liver toxicity may develop in 1 to 4 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 (particularly, 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. Generally the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity.

Drug nomograms are available that will estimate a risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion. To determine the risk of potential hepatotoxicity, the paracetamol level should be 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.

Treatment

Initial measures

The treatment for uncomplicated paracetamol overdose, similar to any other overdose, is gastrointestinal decontamination. In addition, acetylcysteine administration plays an important role. There is considerable room for physician judgement regarding gastrointestinal decontamination with gastric lavage and/or activated carbon administration. Paracetamol absorption from the gastrointestinal tract is complete within 2 hours under normal circumstances. This is somewhat slowed when it is ingested with food. Syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated carbon and oral acetylcysteine. Gastric lavage is helpful within the first 2 to 4 hours of paracetamol ingestion.

Activated carbon is often more helpful than gastric lavage. Activated carbon absorbs paracetamol and reduces its gastrointestinal absorption. Administering activated carbon also poses less risk of aspiration than gastric lavage. Previously 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. Other studies have shown that activated carbon seems to be beneficial to the clinical outcome. There is uniform agreement on administering activated carbon within the first 4 hours of paracetamol overdose, although some have suggested the most benefit if given with 2 hours. However, administering activated carbon later than this can be considered in patients who 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 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.

Acetylcysteine

Acetylcysteine 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. If given within 8 hours of ingestion, NAC reliably prevents toxicity. If NAC is started more than 8 hours after paracetamol 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 increase dramatically.

In United States practice, intravenous (IV) and oral administration are considered to be equally effective. However, IV is the only recommended route in Australian and British practice. Where oral acetylcysteine is required, the inhalation formulation of acetylcysteine (Mucomyst) is often given orally. The respiratory formulation can also be diluted and filter sterilized by a hospital pharmacist for IV use, however this is an uncommon practice. Intravenous acetylcysteine (Parvolex/Acetadote) can be used as a continuous intravenous infusion over 20 hours (total dose 300 mg/kg) in patients presenting within 10 hours after ingestion. Recommended administration involves infusion of a 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg infusion over 4 hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol.

In clinical practice, if the patient presents more than 8 hours after the paracetamol overdose, then activated charcoal is probably not useful, and acetylcysteine should be started immediately. In earlier presentations the doctor can give charcoal as soon as the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory. If the patient presents less than 8 hours after paracetamol overdose, the risk of serious hepatotoxicity has been rare. If repeat doses of charcoal are indicated because of another ingested drug, then subsequent doses of charcoal and acetylcysteine should be staggered every two hours. Acetylcysteine is most effective if given early, but still has beneficial effects if given as late as 48 hours after paracetamol ingestion.

In general, oral acetylcysteine is given as a 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 more doses. Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odour and its tendency to cause nausea and vomiting. It may be diluted to a 5% solution, from its marketed 10% or 20% solutions, to improve palatability.

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 17 dose regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard 17 doses until hepatic function improves or until the patient has a liver transplant.

Prognosis

The mortality rate from paracetamol overdose increases 2 days after the ingestion, reaches a maximum on day 4, 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 of < 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 3 to day 4. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality) while a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).

Veterinary use

Paracetamol is extremely toxic to dogs and cats, and should not be given to them under any circumstances. Cats lack the necessary enzymes to safely break paracetamol down and tiny fractions of a normal tablet for humans may prove fatal. Any cases of suspected ingestion should be taken to a veterinarian immediately for detoxification. There are no home remedies, and while dogs have a greater chance of survival than cats regardless of the amount of paracetamol consumed, the amount of irreversible liver failure is dependent on how quickly veterinary intervention begins. As with humans, acetylcycsteine (Mucomyst) and cimetidine (Tagamet) can stop ongoing liver damage, but neither can reverse damage done.^*

Cultural references

Acetaminophen has even made it into pop lyrics, for instance the song 'Girl, You Have No Faith In Medicine' by the White Stripes. This is an ironic song about a discussion between someone who likes to take pills for every occasion and someone who does not. The drug is the subject of the song 'Pretty Paracetamol' by Fisher-Z and appears in the title of the song 'Monday - Paracetamol' by Ulrich Schnauss.

Paracetamol is also mentioned in the song 'Goldfish and Paracetamol' by the band Catatonia.

The band Snow Patrol also has a song named 'Days without Paracetamol' on their 'Songs for Polarbears' album.

The British band Bush have a song 'Personal Holloway' from the album 'Razorblade Suitcase' that suggests non-recommended consumption paracetamol: "She's blue in the face again / Paracetamol / Burn the darkness all away".

References

External links

Amides | Phenols | Analgesics | Antipyretics | Over-the-counter substances

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