Acetaminophen (APAP) is a common over-the-counter (OTC), antipyretic, anti-inflammatory, analgesic that is more commonly known as Tylenol®, a product of Johnson & Johnson1. Overseas the drug is called paracetamol and is manufactured and sold by countless generic drug makers.
A number of concerns regarding the safety of APAP have arisen over the past several years, including liver and kidney toxicity and adverse cardiovascular and cardiopulmonary effects. This essay will provide an overview of APAP, its uses, and safety issues, with an emphasis on the cardiopulmonary system.
Mechanisms of APAP Activity
The analgesic and antipyretic activity of APAP was thought to be similar to other non-steroidal anti-inflammatory medications because it was believed to inhibit prostaglandin (PGE2) synthesis2,3. This assumption has not withstood the test of time, for either APAP or other popular OTC non-steroidal anti-inflammatory drugs (NSAIDs). The main evidence against NSAIDs affecting PGE2 synthesis is the lack of a dose response and reduction in the urinary excretion of prostaglandin metabolites.
A stronger candidate for NSAID-mediated analgesia is the endogenous opioid pathways, otherwise known as the endocannibinoid system2. This is based on the findings that an APAP metabolite synthesized in the brain prevents cellular uptake of at least one endogenous opioid, thus increasing its effective extracellular concentration. In addition, an antagonist for endocannibinoid receptors blocked the analgesic effects of APAP.
A substantial body of research also supports the involvement of the serotonergic (5-HT) system in mediating the analgesic effect of APAP2. Increased 5-HT concentrations in specific regions of the brain were triggered by APAP and with prolonged APAP treatment 5-HT receptor concentrations were reduced. The latter effect probably reflects central adaptation to prolonged higher concentrations of central 5-HT. In addition, depletion of central 5-HT blocked the analgesic effect of APAP, as did a 5-HT receptor antagonist.
Nitric oxide (NO) is a signaling molecule essential for a number of biological processes, including nociception, inflammation, and the contractile activity of vascular tissue2. APAP is capable of inhibiting NO synthesis and nitric oxide synthase (NOS) protein expression in a dose-dependent manner, but the effect appears to be tissue-specific since APAP had no effect on cytokine-induced NO production by cardiac fibroblasts.
The analgesic effect of APAP, as well as NSAIDs, is therefore likely dependent on a number of different pathways involved in nociception, including the endocannibinoid, 5-HT, and NO systems2. This does not imply though, that the anti-inflammatory activity of APAP also relies on these systems. In fact, studies have revealed that the two activities can be distinguished at least temporally.
The anti-inflammatory effects of APAP and other NSAIDs had been attributed to their ability to inhibit specific cyclooxygenase (COX) activity2. This was based on a number of studies, including a large cohort study that found APAP increased the relative risk of adverse cardiovascular events by 1.68 (95% CI, 1.10-2.58) in healthy women using 15 or more tablets (? 500 mg) per week4. The authors of this study concluded that APAP probably altered COX activity sufficiently to create prothrombotic conditions. In the years since this study was performed though, this mechanism has failed to be validated in vitro or in vivo4. For example, the typical dosage levels required for NSAID-induced analgesia had no effect on PGE2 and thromboxane metabolite levels, or bleeding time, platelet aggregation, or thrombin synthesis in a microvascular injury model2. In addition, it has been shown that APAP specifically inhibits COX-3, and not COX-1 or -2, which explains the relative absence of gastrointestinal side effects3. The mechanism by which APAP and NSAIDs increase the risk of adverse cardiovascular events is therefore still unknown.
APAP Indications and Recommended Dosages
The analgesic efficacy of APAP appears to depend on its ability to influence several signaling systems at once, which may explain why it is so effective. For example, low back pain can be the result of several of these systems being activated at once5. Of the many analgesic choices available to patients suffering from chronic pain, APAP offers one of the best safety profiles and is well-tolerated. The maximum recommended daily dosage is 4 grams (g) total and given in 0.5-1 g doses spread evenly throughout the day, but by no means should patients start at this dosage6,3. Patients suffering from mild to moderate musculoskeletal pain, such osteoarthritis, can benefit from taking APAP alone and is generally considered the first choice for treatment of mild, chronic pain6.
Patients suffering from moderate to severe pain may benefit from drugs that combine APAP with other analgesics5. APAP plus codeine is available by prescription, but the risk of side effects and abuse increases accordingly. APAP plus Tramadol, a synthetic opioid, offers a similar analgesic profile as APAP plus codeine, but with an improved safety profile and less severe side effects. The tramadol/APAP combination is especially useful for the 10% that can't metabolize opiate drugs because they lack the CYP2D6 enzyme. Both of these combination drugs require close clinical supervision to minimize the chances of overdose due to the development of tolerance or addiction.
APAP is the most commonly used OTC analgesics/antipyretics for children under the age of 127. Table 1 shows the dosing recommendations for newborns to 12-year-olds. Infant formulations are generally three times as concentrated as the oral suspensions used for older children and are therefore a common source of overdosing by parents. Chewable tablets, meltaways, and suppositories are also available for children, but the use of suppositories is not recommended by pediatricians because the dosage delivered is unreliable.
APAP Contraindications and Major Side Effects
Patients with a history of liver disease, malnutrition, or alcohol dependence should be made aware that decreased liver function can render them more susceptible to APAP-induced liver failure3. The liver is the primary pathway for the body to metabolize APAP for excretion, so compromised liver function can lead to the development of toxic plasma levels of this drug. Although the difference between safe (< 4 g/day) and toxic (>10 g/day) APAP levels is relatively large for a healthy person, this difference can shrink or disappear in patients with compromised liver function. Unfortunately, once symptoms of hepatotoxicity become severe enough for the patient to seek medical help the chances that they will survive an already damaged liver and cerebral edema is reduced significantly.
Pregnancy is not a countraindication for APAP use, nor is breast-feeding3, and the only known drug interaction is an agonist interaction with warfarin. The main side effects of APAP are skin rashes and blood disorders, although these are rare, and APAP is generally considered safer to use than NSAIDs and aspirin because of a lack of potentially serious gastrointestinal problems3.
APAP Overdose Prevalence and Causes
The biggest health risk that APAP use represents is hepatotoxicity due to overdose. The most recent data available (1993-1999) shows that approximately 56,000 emergency room (ER) visits (also see Fig. 1), 26,000 hospital stays, and 458 deaths per year are the result of APAP overdose9, which made APAP the number one cause of poisonings during this period8. Overall, the number of acute liver failures that can be attributed to APAP increased from 28% to 51% between 1998 and 20038.
The majority of such overdoses represented suicide attempts, but 14-30% were estimated to be unintentional10. The prevalence of unintended APAP overdoses can be explained by recent findings that show 25% of adult (> 12 yrs of age) prescription APAP users were consuming over 4 g/per day between 2001 and 2008, and 2-3% were using more than 10 g/day9. Another factor that was found to contribute to APAP overdose was combination drugs, such as APAP plus tramadol or codeine, which in individuals that have become tolerant to the analgesic effects of the narcotic may be taking too much APAP in an attempt to regain prior levels of pain relief. For this reason, the U.S. Federal Drug Administration in early 2011 limited APAP doses in these combination drugs to 325 mg per dose9.
APAP-induced hepatotoxicity has also been observed in adults taking less than 4 g/day. Compromised liver function, liver disease, a history of alcohol abuse, malnutrition, and use in combination with other drugs such as acetaminophen, are known or suspected contributing factors for increasing the toxicity of APAP 10.
APAP doses above 150 mg/kg or 70 mg / lb can cause acute liver failure in children, but the effects of aging on the glutathione pathway provide an additional margin of error that adults do not enjoy. As in adults, excessive levels of APAP overwhelm the glutathione synthesis pathway and hepatocellular necrosis results. A Scottish study monitored APAP prescriptions for 36,000 children between the ages of 0-12 during 200612. During the study period, 4423 prescriptions were issued for 2761 children (7.7% of the study cohort). Of these, 22.75% were for off-label use, 13.3% were underdosed, and 4.4% were overdosed. The age group at highest risk (p < 0.001) for being overdosed was 1-3 months, representing over a fifth of all overdoses. Overdosing was attributed to poor, inaccurate, or missing dosing instructions, the belief that APAP is…