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Revision as of 11:50, 10 May 2004 by Ksheka (talk | contribs) (=Natural history= Hedge our bets...)(diff) ← Previous revision | Latest revision (diff) | Newer revision → (diff)The drug acetaminophen (AE), or paracetamol (BE), is an analgesic (a pain reliever). It is one of the most popular antipyretic and analgesic agents in the world. It is also used in numerous cold and flu medications and is a major ingredient in many prescription analgesics. It is remarkably safe in standard doses, but because of its wide availability, deliberate or accidental overdose is not uncommon.
 Acetaminophen (Paracetamol) | |
| N-acetyl-para-aminophenol | |
| Molecular Weight | 151.17 |
| Empiric Formula | C8H9NO2 |
| Metabolism | Liver |
Acetaminophen, 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 or NSAIDs. Acetaminophen has the advantage of not irritating the lining of the stomach or affecting coagulation.
Etymology
The words acetaminophen and paracetamol both come from the chemical name for the compound, N-acetyl-para-aminophenol (or para-acetyl-amino-phenol): N-acetyl-para-aminophenol and para-acetyl-amino-phenol.
History
Acetaminophen was first synthesized in 1873 by Harmon Northrop Morse, but was not used medically until 1893. It did not gain popularity until after World War II when it was found to be a metabolite of phenacetin (this fact was first discovered in 1899 and rediscovered in 1948), offering similar effects but markedly less toxicity.
On September 30th 1982, the first of seven individuals died in metropolitan Chicago after ingesting acetaminophen capsules (sold under the name Extra Strength Tylenol) that contained cyanide. The capsules were later found to contain 65 milligrams of cyanide each, more than 10,000 times the lethal dose to an adult. This is the first known deliberate tampering of a medication that led to death.
Johnson & Johnson, the producer of Extra Strength Tylenol, issued a nation-wide recall of Tylenol capsules, at an estimated loss of 100 million dollars. The company also advertised in the national media for individuals to not consume any products that contained Tylenol. When it was realized that only capsules were tampered with, Johnson and Johnson offered to exchange all tylenol capsules already purchased by the public with solid tablets. Johnson and Johnson was praised by the media at the time for its responsible handling of the entire incident.
This tragic event made the pharmaceutical industry realize that the capsule form was easy to contaminate, since it was possible for a foreign agent to be placed within a capsule without obvious signs that it was tampered with. Within the year, the FDA introduced more stringent regulations to avoid product tampering. This led to the eventual replacement of the capsule with the solid "caplet" as a drug delivery form.
The U.S. patent on acetaminophen 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".
Overview
In North America, acetaminophen is sold in generic form or under a number of trade names: for instance Tylenol (McNeil-PPC, Inc), Anacin-3 and Datril, while it is known as Panadol in parts of Asia and Australasia. In some formulations acetaminophen is combined with the opiate codeine. It relieves headaches and other minor aches and pains, and lowers fever.
It is commonly administered in tablet, liquid suspension, or suppository form. The common adult dose is 500mg to 1000mg four times a day. Doses above 150mg/kg or 7.5g for an adult is likely to cause hepatotoxicity.
Because of the widespread availability of acetaminophen, it's effectiveness is often underestimated.
Mechanism of action
Acetaminophen, like aspirin and NSAIDs, works by reducing the activity of the cyclo-oxygenase 2 (COX) enzyme which produces prostaglandins. While the other drugs operate as competitive inhibitors and directly block the active site of COX, acetaminophen blocks COX indirectly. This indirect blockade is effective in the brain and endothelial cells but not in platelets and immune cells which have high levels of peroxides.
Thus, acetaminophen does not reduce inflammation or act as an anticoagulant, while aspirin does. Aspirin's unique anticoagulant effect is due to acetylation of platelet cyclooxygenase.
Metabolism
Acetaminophen 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 P-450 enzyme system. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine), not acetaminophen 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.
Toxicity
Overview
Overdoses of acetaminophen can lead to liver failure and a painful death if untreated. Because of the wide over-the-counter availability of the drug, it is often used in suicide attempts. Acetaminophen should not be taken after alcohol consumption, because the liver, when engaged in alcohol breakdown, cannot properly dispose of acetaminophen, thus increasing the risk of hepatotoxicity.
Mechanism of action
As mentioned above, acetaminophen is mostly converted to inactive compounds by conjugation with sulfate and glucuronide, with a small portion being metabolized via the cytochrome P-450 enzyme system. The cytochrome P-450 system oxidizes acetaminophen to produce 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 acetaminophen toxicity, the sulfate and glucuronide pathways become saturated, and more acetaminophen is shunted to the cytochrome P-450 system to produce NAPQI. Subsequently, 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 acetaminophen is highly variable. In adults, single doses above 10 grams or 140 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, unintentional acetaminophen overdose in children rarely causes illness or death. This may be due in part to the immature cytochrome P-450 enzyme system in children.
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. Chronic ingestion of barbiturates and use of anti-tuberculous medications (especially isoniazid) also increase the risk of hepatotoxicity, possibly due to stimulation of the cytochrome P-450 enzyme system. Chronic alcoholism may also be a risk factor.
Natural history
Individuals who have overdosed on acetaminophen generally have no specific symptoms for the first 24 hours. Although anorexia, 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 worse 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 acetaminophen. 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 risk of end stage renal disease is also increased in patients with underlying renal disease who have a cumulative lifetime intake of more than 300 grams of acetaminophen.
The prognosis of acetaminophen 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. 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 acetaminophen overdose, when AST and ALT exceed 1000 IU/L, acetaminophen-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 acetaminophen-induced hepatotoxicity.
Drug nomograms are available that will estimate a risk of toxicity based on the serum concentration of acetaminophen at a given number of hours after ingestion. To determine the risk of potential hepatotoxicity, the acetaminophen level should be traced along the standard nomogram. The acetaminophen level should not be drawn in the first four hours after ingestion since acetaminophen may still be in the process of being absorbed from the gastrointestinal tract.
Treatment
The treatment for uncomplicated acetaminophen overdose, similar to any other overdose, is gastrointestinal decontamination. In addition, N-acetylcysteine (NAC) administration (either intravenous or oral) plays an important role. There is considerable room for physician judgment regarding gastrointestinal decontamination with gastric lavage and/or activated charcoal administration. Acetaminophen absorption from the gastrointestinal tract is complete within 2 hours under normal circumstances. This is somewhat slowed when it is ingested with food. Ipecac has no role in acetaminophen overdose because the vomiting it induces delays the effective administration of activated charcoal and (oral) NAC. Gastric lavage is helpful within the first 2 to 4 hours of acetaminophen ingestion.
Activated charcoal is often more helpful than gastric lavage. Activated charcoal absorbs acetaminophen well and therefore reduces its gastrointestinal absorption. Administering activated charcoal also poses less risk of aspiration than gastric lavage. Previously there was reluctance to give activated charcoal in acetaminophen overdose, because of concern that it may also absorb NAC. Studies have shown that no more than 39% of oral NAC is absorbed when they are administered together. Other studies have shown that activated charcoal seems to be beneficial to the clinical outcome. There is uniform agreement on administering activated charcoal within the first 4 hours of acetaminophen overdose; administering activated charcoal after the first 4 hours is a clinical judgment and is considered a benign therapy. If concern exists that other drugs were ingested with the acetaminophen, then activated charcoal should be given. There are conflicting recommendations regarding whether to change the dosing of oral NAC after the administration of activated charcoal, and even whether the dosing of NAC needs to be altered at all.
NAC presumably works by supplying sulfhydryl groups to react with the toxic metabolite so that it does not damage cells. If given within 8 hours of ingestion, NAC reliably prevents toxicity. If NAC is started more than 8 hours after acetaminophen ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver had already begun, and the risk of acute hepatic necrosis and death increase dramatically.
Oral NAC (available in the United States under the name Mucomyst) is a safe drug, is indicated in acetaminophen overdose during pregnancy, and life-threatening adverse reactions do not occur. The manufacturer’s recommendation is avoidance of administration if an encephalopathy is present, due to the theoretical concerns that it may worsen encephalopathy. Intravenous NAC is available outside the United States of America (under the name Parvolex) and is available in limited areas of the United States as an investigational drug. It is an option in patients who cannot tolerate enteral NAC or for whom enteral intake is contraindicated. Intravenous NAC is associated with allergic reactions such as anaphylaxis and bronchospasm.
In clinical practice, if the patient presents more than 8 hours after the acetaminophen overdose, then activated charcoal is probably not useful, and NAC should be started immediately. In earlier presentations the doctor can give charcoal as soon as the patient arrives, start giving NAC, and wait for the acetaminophen level from the laboratory. If the patient presents less than 8 hours after acetaminophen 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 NAC should be staggered every two hours.
In general, oral NAC is given enterally as a 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 more doses. NAC can be difficult to administer because of its taste and its tendency to cause nausea and vomiting. To maximize tolerance, it can be diluted down to a 5% solution from its commercially available 10% or 20% solutions.
Baseline laboratory studies should include bilirubin, AST, ALT, and prothrombin time (with INR). Studies should be repeated at least daily. Once it has been determined that a potentially toxic overdose has occurred, NAC must be continued for the entire 17 dose regimen, even after the acetaminophen level becomes undetectable in the blood. If hepatic failure develops, NAC should be continued beyond the standard 17 doses until hepatic function improves or until the patient has a liver transplant.
The mortality rate from acetaminophen overdose starts to climb 2 days after the ingestion, reaches a maximum on day 4, and then gradually decreases. Patients with a poor course should be identified early and transferred to a center capable of liver transplantation.
Acidemia is the most ominous 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. Once 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).
References
- 1. Wolnik KA, Fricke FL, Bonnin E, Gaston CM, Satzger RD. The Tylenol tampering incident--tracing the source. Anal Chem 1984;56:466A-8A, 470A, 474A.
- 2. Boutaud O, Aronoff DM, Richardson JH, Marnett LJ, Oates JA. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proc Natl Acad Sci U S A. 2002 May 14;99(10):7130-5. (Medline abstract), (Full text)