The major metabolite of phenacetin.

Also known as paracetamol or N-acetyl-p-amino phenol (APAP).

Paracetamol is predominantly a centrally acting analgesic  which mediates its effect by action on descending serotoninergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release, which inhibits release of pain mediators.

It decreases cyclo-oxygenase activity.

Most or all of the therapeutic efficacy of paracetamol is due to a metabolite, AM404, which enhances the release of serotonin and inhibits the uptake of anandamide.

Most used analgesic and antipyretic drug worldwide.
Currently more than 52 million people in the US consume acetaminophen on a weekly basis: many unaware that the medications they are taking contain acetaminophen.

Indicated for relief of fever and pain.

It is he most widely used over-the-counter medicine for musculoskeletal conditions.

Recommended doses 325-650 mg every four to six hours or 1000 mg three to four times per day, while the dose of for children less than 12 years old is 10-15 mg/kg/dose every 4-6 hours.

Maximum daily dose is 4 gms for adults and 90 mg/kg for children.

Toxic single dose in adults is 150 m/kg or approximately 7 grams.

In overdose, can lead to hepatotoxicity and acute renal tubular necrosis.

There is a narrow safety range between therapeutic effect and toxicity.

Annually acetaminophen is responsible for 112,000 Poison Center calls, 59,000 emergency department visits and 38,000 hospitalizations.

Approximately 38,000 hospitalizations annually in the United States for overdoses, and half of these admissions are result of unintentional overdose.

The annual percentage of acetaminophen related acute liver failure rose from 20% in 1998 to 51% in 2003.

It is the leading cause of acute liver failure in the US and other high income countries.

The majority of cases of acute liver failure are related to deliberate self harm, close to half are related to unintentional overdose or therapeutic misadventure.

Patients who take more than the recommended dose of 4 g per day for greater than 12 years or who consume alcohol while taking acetaminophen are at risk for hepatotoxicity, ranging from blood abnormalities in liver function tests to acute liver failure and even death.

Threshold for toxicity may be lower in alcoholic patients.

Recommended doses 325-650 mg every four to six hours or 1000 mg three to four times per day, while the dose of for children less than 12 years old is 10-15 mg/kg/dose every 4-6 hours.

Side effects minimal at recommended doses.

Side effects include: hemolytic anemia, pancytopenia, leukopenia, thrombocytopenia, hypoglycemia, and jaundice.

Risk of rare but serious skin reactions.

Can cause increase in chloride, uric acid, glucose, bilirubin, alkaline phosphatase, hyponatremia, decreased bicarbonate and hypocalcemia.

Patients may be at higher risk of hepatotoxicity following fasting, starvation, chronic alcohol abuse.

Hepatotoxicity is rare with doses less than 8 g a day, even in the presence of liver disease.

Hypersensitivity reactions are extremely rare.

Urticaria and erythematous skin changes and fever may occur.

Other complications of acetaminophen toxicity include coagulopathy and deafness.

Lowers body temperature by inhibiting prostaglandin E2 synthesis in the brain.

Rapidly absorbed across the stomach and small intestine, with metabolism in the liver and elimination in the urine.

Inhibits COX-3 activity in the brain where it is expressed in the cerebral cortex.

Inhibits prostaglandin synthesis, specifically synthetase, in the CNS and peripherally blocking the pain impulse.

Inhibits heat regulation center in the hypothalamus providing antipyretic effects.

A weak inhibitor of COX-1 and COX-2 peripherally and is without anti-inflammatory activity.

At doses of more than 4 gm a day in adults can lead to nephrotoxicity and hepatotoxicity.

Hospitalized adults experienceba supratherapeutic dosing of acetaminophen in hospitals of 4% (Zhou L et al).

Associated with hepatotoxicity at massive doses.

A leading cause of acute liver failure in the United States.

Toxic single dose for adults is 105 mg/kg.

Approximately 5% of therapeutic dose is metabolized by cytochrome P450 2E1 to the electrophile N-acetyl-p-benzoquinone imine (NAPQI).

NAPQI is detoxified by interaction with glutathione to form cysteine and mercapturic acid conjugates.

When taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body.

NAPQI is normally conjugated by glutathione, but when taken in excess, the body’s glutathione reserves are not sufficient to inactivate it, and the metabolite damages hepatocytes.

This may lead to severe liver damage and even death by acute liver failure.

As long as adequate glutathione is present the liver remains protected from injury.

Acetylcysteine prevents hepatic injury from acetaminophen by restoring hepatic glutathione.

With associated liver failure acetylcysteine improves hemodynamic, cerebral edema oxygen utilization of liver function.

When excessive doses are given the hepatic glutathione liver stores can be depleted with liver injury as a result.

Most important cause of acute liver failure in Europe and U.S.

With acute liver failure 85% of patients die, if not given a liver transplantation.

In recent years unintentional overdoses have been the major cause of acute liver failure with a dose as low as 7 gm a day.

Some patients such as those fasting, taking isoniazid, barbiturates, zidovudine or consume excess alcohol can develop liver damage with moderately elevated doses.

4 grams a day dosage tolerated by most patients without adverse effects.

Associated with the prolongation of the half-life of warfarin.

In fasting patients, with alcohol exposure, in the presence of liver disease, in the presence of drugs like anticonvulsants and in frail elderly, liver toxicity can occur with recommended doses.

In dosage of 6000 mg daily can lower body temperature by 0.3-0.4 ‘C in patients with ischemic stroke.

Recommended doses of 4 gm per day associated with elevations of ALT enzymes even in the absence of measurable serum acetaminophen concentrations.

Watkins et al report 27% of patients given therapeutic doses of acetaminophen had increased aminotransferase concentrations.

Poisoning responsible for more than 70,000 healthcare visits, and approximately 300 deaths in 2005.

Poison Control Centers reported in 2004 132,683 incidents involving this agent or in combination with another product with 327 fatalities.

Involved in 28%-51% of liver toxicity associated liver transplants.

Poisoning may be second to massive single overdose or to excessive use for therapeutic intent.

When taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body and is normally conjugated by glutathione, but when taken in excess, the body’s glutathione reserves are not sufficient to inactivate the toxic NAPQI.

This metabolite, NAPQI is then free to react with key hepatic enzymes damaging hepatocytes, leading to severe liver damage and even death by fulminant liver failure.

Poisoning categorized in four stages: preclinical, hepatic injury, hepatic failure and recovery.

Transient liver injury may develop during the preclinical stage, but there is full recovery.

Patients who develop hepatic failure have a mortality rate of 20-40%.

High use associated with almost twofold increase in the risk of hematologic malignancies other than CLL/SLL.

In patients with acetaminophen poisoning, shorter acetylcysteine treatment regimens result in less risk of discomfort, vomiting, and the need for rescue antiemetics than standard regimens.

Patients on the modified regimen track received a dose of 300 mg/kg over 12 hours, while those on the standard regimen of treatment received the same dose over 20-25 hours (Bateman D et al).

A meta analysis of,13 randomized controlled trials designed to investigate the safety and efficacy of acetaminophen in the management of lower back or neck pain and osteoarthritis. showed it is not effective and offers little value.

Meta-analyses of randomized trials of acetaminophen in persons with knee osteoarthritis suggest minimal efficacy.

In a randomized study of 700 patients with fever treated with intravenous acetaminophen or placebo did not affect the number of ICU free days open (Young P et al).

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