Acetaminophen overdose and cardiopulmonary system effects

Tylenol Overdose

Health Sciences 101

The Health Impact of Acetaminophen Overdose

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.

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 harmless due to its OTC designation, and highly concentrated infant formulations.

Signs of APAP Overdose

During the first 24 hours (Stage 1) after ingesting too much APAP the patient will likely experience gastrointestinal distress, including pain, nausea, and vomiting8. The patient may also be lethargic, sweating profusely, and appear pale. Liver tests are typically normal, but there may be mild elevations in liver enzymes after 8-12 hours. Some patients may be, or become, asymptomatic during the same period, which makes it difficult for clinicians to diagnose the early stages of APAP-induced liver failure. The serum concentration of APAP should be determined as soon as possible so that the antidote, N-acetylcysteine, can be administered within 8-10 hours after acute APAP ingestion (see Fig. 2).

Stage 2, the latent period, occurs between 24 to 72 hours. During this phase laboratory tests for liver function become abnormal8. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT, > 1,000 IU/ml)) increase in all patients by 36 hours, with AST levels reaching as high as 10,000 IU/ml and in some patients the AST/ALT ratio is >1. Bilirubin (> 10 mg/dl) and prothrombin time (PT/INR) also increase and patients may present with right upper quadrant pain and jaundice.

Stage 3 occurs between 72 and 96 hours as symptoms of hepatocellular necrosis become obvious8. Common signs and symptoms include anorexia, nausea, vomiting, abdominal pain, malaise, confusion, and jaundice. Laboratory tests will reveal extremely high levels of AST and ALT, which peak around 72 hours after ingestion. Over 50% of patients will experience renal insufficiency due to tubular necrosis, resulting in proteinuria, hematuria, and granular casts. Pancreatitis may also develop, leading to high insulin levels and lactic acidosis. A poor prognosis is associated with the development of acute liver failure, renal failure, hypoglycemia, PT/INR > 100 seconds, progressive encephalopathy, cerebral edema, and metabolic acidosis (pH < 7.3). Death can result from cerebral herniation, multiple organ failure, or sepsis, and usually occurs 3-5 days after APAP ingestion.

About 70% of patients will survive the first three stages of acute liver failure and enter Stage 4, the recovery phase8. Most recover completely by 7 days and complete functional recovery is generally achieved.

APAP and Cardiopulmonary Insufficiency

APAP is considered the analgesic of choice for anyone suffering from mild pain, so its use is prevalent among older adults. However, age-related health problems can compromise organ function, which may in turn complicate the determination of safe APAP levels for this demographic. The glucuronidation of APAP by the liver is the primary metabolic pathway for its elimination and this process requires sufficient delivery of oxygen to hepatocytes to function efficiently13. A case study examining suspected APAP-induced acute liver failure in a 67-year-old male with congestive heart failure revealed that renal and cardiopulmonary insufficiency were probably the primary contributing factors. The patient had no history of liver disease or alcohol abuse, and was taking only 1-3 g of APAP per day. Arterial oxygen saturation when breathing normal air was 94%, just below the normal lower limit of 95%.

A more recent study in Switzerland examined 33 patients with cardiovascular disease who were already using APAP14. The mean age of the study group was 60.5. After receiving a morning dose of APAP (1g) or placebo, blood pressure (BP) and flow-mediated dilation (FMD) were monitored for the next 24 hours. Both systolic and diastolic BP increased significantly compared to placebo (p < 0.05), but even though heart rate also increased, statistical significance was not reached due to the small size of the study group. Endothelial function, endothelial progenitor cells, and platelet function were not significantly affected, but the data suggested a trend downward in endothelial function at the end of 2 weeks. The authors concluded that the impact of APAP on cardiovascular function needs to be studied in a larger cohort and over a longer period to better understand the significance of these findings

Conclusions

APAP is one of the most widely used antipyretic/analgesic medications in the world, but the OTC designation conveys a message of safety to the public that may not be fully deserved. For example, healthy women taking over 7.5 g/day are more likely to suffer an adverse cardiovascular event4, even though this is below the generally assumed acute toxic level of 10 g/day. Therapeutic doses of APAP can also increase BP and heart rate14, which may explain the increased risk of adverse cardiovascular events. When these study results are considered in light of the fact that 84% of all infants in the United Kingdom receive APAP during the first 6 months of life12, it is hard not to be concerned about lifelong cardiopulmonary health. Cardiopulmonary and/or renal insufficiency, in the absence of liver disease or history of malnutrition or alcohol abuse, may be sufficient to predispose individuals for developing toxic levels of APAP within the therapeutic range13. Overall, APAP is safe to use by healthy adults and children but the dangers this drug poses to the rest of the population are significant. Much more research needs to be done to determine safe dosages for everyone.

Weight (lb)

Age

Doses every 4 hr (mg)

Concentrated drops (80 mg/0.8 mL)

Suspension (160 mg/5 mL)

6-11

0-3 mo

40

0.4

N/A

12-17

4-11 mo

80

0.8

2.5

18-23

1-2 yr

1.2

3.75

24-35

2-3 yr

1.6

5

36-47

4-5 yr

2.4

7.5

48-60

6-8 yr

N/A

10

60-71

9-10 yr

N/A

12.5

72-95

11 yr

N/A

15

Table: Recommended APAP Dosages for Children Ages 0-12 Years of Age7.

Figure 1: FDA Statistics for Emergency Room Visits due to APAP Overdose.

Figure 2: Potentially Toxic Serum APAP Concentrations8.