Acetaminophen and NSAID Toxicity
Acetaminophen & NSAIDs - Background and Overview
Acetaminophen has been available as an over-the-counter analgesic and antipyretic for over 50 years. More than 100 million people use acetaminophen each year in the U.S. alone, with up to 50 million Americans using acetaminophen-containing products in a given week (Amar 2007). While generally considered a safe therapy when taken below the recommended maximum daily dose of 4 grams, acetaminophen overdoses are not uncommon (Ferner 2011; Amar 2007).
Although most patients recover spontaneously from an acetaminophen overdose, the drug can cause life-threatening liver injury. Acetaminophen accounts for up to 50% of all adult cases of acute liver failure in the U.S. (Craig 2010; Amar 2007). Even in the absence of overt overdose symptoms, therapeutic acetaminophen dosages can still increase the blood concentrations of liver enzymes (markers of liver damage) (Watkins 2006). Other potential negative consequences of acetaminophen include increased fracture risk (Vestergaard 2012), inhibition of testosterone production (Kristensen 2011; Kristensen 2012), and kidney toxicity (Bessems 2001).
NSAIDs are among the most widely used of all drugs, with 20 to 30 billion tablets sold each year in the U.S. alone (Peura 2002; Dal Pan 2009). The prototypical member, aspirin, is one of the oldest analgesics, in use as an anti-inflammatory therapy long before the molecular mechanics of inflammation had been discovered. Low-dose aspirin (e.g. 75-100 mg) is often used to reduce the risk of cardiovascular events in high-risk patient populations (Mills 2012). Regular use of aspirin has also been associated with a significantly reduced risk of several cancers (see below) (Algra 2012).
The anti-inflammatory properties of NSAIDs are due to their inhibition of the cyclooxygenase (COX) enzymes, which catalyze the synthesis of localized pro-inflammatory signaling molecules called prostaglandins (Toussaint 2010).
The two COX enzymes with well-defined roles in humans are COX-1 and COX-2. COX-2 is normally inactive, but can be turned on during inflammation to produce pro-inflammatory prostaglandins. In contrast, COX-1 is normally active in many tissues, where it has roles unrelated to inflammation (e.g., clotting function in blood platelets, mucus production from cells lining the GI tract) (Toussaint 2010; Conaghan 2012). The inhibition of prostaglandins in the central nervous system also raises the pain threshold and acts on the hypothalamus to reduce body temperature (Amar 2007).
Non-selective NSAIDs (aspirin, naproxen [e.g., Aleve®], ibuprofen [e.g., Advil®], diclofenac [e.g., Cambia®], and indomethacin [Indocin®]) inhibit the activity of both COX enzymes (Conaghan 2012). COX-2 selective NSAIDs (i.e., COX-2 inhibitors or coxibs) inhibit COX-2 more strongly than COX-1, resulting in less gastrointestinal side effects, but potential cardiovascular complications, most notably an increase in the risk of heart attack due to increased blood clotting propensity (see below) (Conaghan 2012).