Acetaminophen Dosing & Pathophysiology
People don't realize that acetaminophen is a narrow therapeutic index drug. The toxic dose is not much higher than the therapeutic dose.

Just 6 g/day for 2 days can cause liver toxicity in some patients.

And it's easy for patients to get too much due to multiple prescribers or multiple ailments...Vicodin for pain, acetaminophen for headaches, Theraflu for colds and flu, Tylenol PM for sleep, etc.

In fact, half of acute liver failures due to acetaminophen are due to Unintentional overdoses.

You'll hear talk about lowering the maximum recommended dose to 650 mg/dose and 3250 mg/day...down from 1000 mg/dose and 4000 mg/day.

3250 mg/day works out to be 650 mg 5 times a day. Explain that 650 mg works almost as well as 1000 mg for pain...and it's safer.

Experts will debate an even lower dose for people who have three or more drinks per day or have liver disease.

Regulators will consider big changes...limiting acetaminophen products to 325 mg/tab...allowing just ONE strength of pedi liquids...eliminating OTC combo products...and requiring MedGuides for Rxs.

Discourage using Rxs with high doses of acetaminophen...Vicodin ES, Vicodin HP, hydrocodone/acetaminophen 7.5/650, Darvocet-N 100, etc. Explain that these contain 650 to 750 mg acetaminophen per TABLET.

When appropriate, suggest a formulation with just 325 mg/tab...such as all strengths of Norco (hydrocodone/acetaminophen).

Help patients recognize and limit the total they get from ALL their Rxs and OTCs. Don't use "APAP" on labels...people don't know what it is.

Advise heavy drinkers to keep acetaminophen well below 3250 mg/day.
Symptoms of acetaminophen toxicity can resemble flu-like symptoms. So people take more acetaminophen...until it's too late.

Contact the prescriber or poison center if someone takes over 10 g or 200 mg/kg in one day...or 6 g/day or 150 mg/kg for 2 or more days.

Tell people they may need to have their acetaminophen level checked to see if they need treatment to prevent liver toxicity.

Dosing Chart for Acetaminophen

Pathophysiology

The maximum recommended daily dose of acetaminophen is 4 g in adults and 90 mg/kg in children. Toxicity is associated with a single acute APAP ingestion of 150 mg/kg or approximately 7-10 g in adults. The ingested amount at which toxicity may occur may be lower in the settings of chronic ethanol use, malnourishment, or diminished nutritional status, fasting, or viral illness with dehydration, or if substances or medications that are known to induce the activity of the CYP oxidative enzymes are being used. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

Acetaminophen is rapidly absorbed from the stomach and small intestine and primarily metabolized by conjugation in the liver to nontoxic, water-soluble compounds that are eliminated in the urine.

In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to a reactive metabolite, N -acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is renally excreted. Under conditions of excessive NAPQI formation, or reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts.

An ensuing cascade of oxidative damage, mitochondrial dysfunction, and the subsequent inflammatory response propagate hepatocellular injury, death, and centrilobular (zone III) liver necrosis. Similar enzymatic reactions occur in extra-hepatic organs, such as the kidney, and can contribute to some degree of extra-hepatic organ dysfunction.

The antidote for acetaminophen poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and as such, increases glutathione conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP. NAC functions as an anti-inflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide concentrations and promotes microcirculatory blood flow, enhancing local oxygen delivery to peripheral tissues. The microvascular effects of NAC therapy are associated with a decrease in morbidity and mortality even when NAC is administered in the setting of established hepatotoxicity.

NAC is maximally hepatoprotective when administered within 8 hours of an ingestion. When indicated, however, NAC should be administered regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure, even in the absence of measurable serum acetaminophen levels.