Neither acetaminophen itself nor these metabolites are toxic. In overdose situations, this glutathione is rapidly depleted, and free unconjugated NAPQI binds covalently to various hepatocellullar macromolecules, producing a centrilobular hepatic necrosis, which can progress to fulminant hepatic failure. However, acetaminophen is one of the few drugs where the patient may appear normal with no signs and symptoms for the first 24 hours, despite the ingestion of a toxic dose.
Thus all patients who present with a potential overdose of any sort should have an acetaminophen level drawn to rule out co-toxicity with acetaminophen. Stage 2 occurs between 24 to 72 hours and is characterized by right upper quadrant pain, elevation of transaminases and the PT. There may also be deterioration of renal function. Stage 3 is from 72 to 96 hours and is characterized by the sequelae of centrilobular hepatocellular necrosis including hepatic encephalopathy, bleeding diathesis, hypoglycemia and possible death.
Stage 4 begins at 4 days to 2 weeks during which complete resolution of hepatic dysfunction occurs if damage in phase 3 is not irreversible. In summary, acetaminophen toxicity is important because early symptoms may be subtle, and the onset of hepatotoxicity, the major manifestation, is delayed by several days following the ingestion.
Failure to recognize and treat toxicity early results in significant morbidity and mortality. The first acetaminophen level should be drawn at 4 hours post-ingestion, as levels done before this are uninterpretable because absorption and distribution of the drug may not be complete.
If the patient presents greater than 24 hours post-ingestion, the level could be zero despite toxicity so liver function tests should be drawn. To interpret the serum acetaminophen level, the time of ingestion must be established as accurately as possible and the level plotted on the Rumack-Matthew normogram. When in doubt, choose the earliest possible time of ingestion the worst case scenario. The normogram is based on single ingestion in time thus if the patient took the pills over many hours multiple ingestions in time choose the time when the first pills were ingested, which again is the conservative worst case scenario.
The treatment of acetaminophen overdose is relatively straightforward. In the second phase, occurring up to 24 to 48 hours after ingestion, there may be a false sense of recovery as GI symptoms improve or disappear. In addition, laboratory values will begin to show evidence of hepatotoxicity; hepatic enzymes, lactate, phosphate, prothrombin time, and international normalized ratio INR will increase dramatically.
A few patients will progress to phrase three, usually occurring 3 to 5 days postingestion. This phase is characterized by the reappearance or worsening of nausea and vomiting accompanied by malaise, jaundice, and central nervous symptoms including confusion, somnolence, and coma. Although less common, renal insufficiency, as demonstrated by oliguria, can manifest as a result of acetaminophen-induced tubular necrosis.
Jaundice, hypoglycemia, bleeding and coagulation abnormalities, and hepatic encephalopathy will also be evident. Lastly, phase four involves survival and recovery, generally with return of full liver function and no long-term effects.
Because the mechanism of acetaminophen toxicity occurs via the formation of NAPQI, any factors that influence the availability of metabolic enzymes will therefore affect toxicity. Alcohol use, malnutrition, and induction of CYP enzymes by drugs, including long-term treatment with carbamazepine, primidone, rifampin, efavirenz, and St.
Conversely, in chronic alcohol use, ethanol is an inducer of CYP2E1, leading to a potential increase in the formation of NAPQI should an overdose of acetaminophen occur. Another consequence of chronic alcohol use is the depletion of glutathione stores, reducing the last defense against the formation of NAPQI. Although controversial, starvation prolonged fasting and malnutrition are additional risk factors for acetaminophen toxicity.
However, there is also evidence that CYP2E1 function is markedly reduced in this patient population. These effects would thereby counteract each other, potentially resulting in no change in toxicity. Upon presentation, the patient should be thoroughly assessed. A detailed recent drug history should be obtained. Serum acetaminophen levels should ideally be drawn at least 4 hours after ingestion.
Pharmacists can play an important role by gathering pertinent information such as the amount of drug taken, the dosage form ingested, the amount of time that has elapsed since the last ingested dose, and if any other drugs were consumed.
All of these factors are important when analyzing serum acetaminophen concentrations. If the patient presents within an hour of ingestion, gastric decontamination may be considered; activated charcoal is the only GI decontamination method recommended. It should also be avoided in those with an increased risk of aspiration, uncontrolled vomiting, or coingestion of a corrosive or proconvulsant. Acetylcysteine: The mainstay of treatment for acetaminophen toxicity is acetylcysteine.
This agent replenishes hepatic glutathione stores and increases sulfate conjugation, preventing accumulation of NAPQI. Acetylcysteine may prevent hepatic failure from an acetaminophen overdose when administered early enough within hours following an acute overdose but may still be of value up to 48 hours after ingestion.
However, it is rendered ineffective when evaluating possible toxicity due to multiple ingestions over time, when time of ingestion is unknown, or when altered metabolism occurs. Acetylcysteine is available orally and intravenously; the choice is dependent on the clinical scenario. If the patient is doing well yet has not fully recovered after the recommended dosing, acetylcysteine therapy can be continued using either the last oral dose or the last IV infusion rate. Acetylcysteine should be continued beyond the protocol length until acetaminophen concentrations are undetectable, serum AST has normalized or significantly improved, and there is resolution of any evidence of hepatic failure.
Because its unpleasant taste and smell, vomiting frequently occurs with oral acetylcysteine administration. The complicated regimen, length of therapy, and need for multiple health professionals to administer doses at various treatment sites greatly increase the risk for errors.
Another common error identified was the unnecessary administration of acetylcysteine, resulting in unnecessary costs. It is important for healthcare providers to consult with poison centers in cases of acetaminophen overdoses. They can provide the most up to date dosing information and protocols to ensure proper administration of acetylcysteine.
In hopes of increasing safety and reducing toxicity, the FDA has long been updating its recommendations regarding acetaminophen use. In the late s, research demonstrated that acetaminophen was a leading cause of acute liver failure in the U. As years passed and the correlation between acetaminophen and liver toxicity became even more evident, the FDA convened a meeting to act upon these findings. In , the FDA Advisory Committee recommended that a liver toxicity warning be placed on all acetaminophen-containing products.
In , new labeling was developed to help patients easily identify which products contained acetaminophen, reducing the potential for accidental overdoses. A black box warning was later placed on all prescription acetaminophen products emphasizing the potential risk for severe liver injury, and a warning for rare but serious anaphylaxis and other hypersensitivity reactions was implemented.
The FDA has also announced that as of January , the amount of acetaminophen found in prescription combination products must be limited to mg per tablet or capsule. Although progress has been made, some things are still to be determined. Efforts are also being made to improve product labeling, enhance patient education, create a universal pediatric formulation, eliminate acetaminophen combination products, and reduce the strength of OTC acetaminophen products to mg per tablet with a maximum single dose of mg.
Pharmacists are in a position to effectively promote the safe use of acetaminophen. Many patients are not aware of the maximum daily dose of acetaminophen and the potential for toxicity.
Pharmacists must take a proactive role in educating patients who purchase OTC acetaminophen products. In addition, pharmacists should recommend that patients contact the national Poison Help Line if they suspect an acetaminophen overdose. The toll-free number is These specialists will be able to help assess and manage the potential acetaminophen overdose. Such activities will minimize the risk of inappropriate dosing, duplication of therapy, and inappropriate drug use.
Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. Pharmacoepidemiol Drug Saf. Frequent monthly use of selected nonprescription and prescription non-narcotic analgesics among U. In a retrospective study, this model was able to accurately predict whether the overdose would lead to fatal liver damage. Our model is complementary to the work of[ 10 ] since it focuses on the detailed biochemical mechanisms by which of APAP is detoxified in the liver under both normal and overdose situations.
The mathematical model consists of 21 differential equations for the variables listed in Table 1. The differential equations corresponding to the reactions diagramed in Figure 1 are listed below. Lower case p , l , t , and u refer to plasma, liver, tissue and urine respectively. We use lower case italic abbreviations in the differential equations and other formulas so that they are easy to read and are not confused with enzyme names which are in caps. Full names for the enzymes appear in the legend to Figure 1.
Reaction velocities or transport velocities begin with a capital V followed by the name of the enzyme, the transporter, or the process as a subscript. For example, V lSULT lapap , lpaps is the velocity of the sulfation reaction in the liver, which depends on the concentrations of the substrates, lapap and lpaps. After the differential equations, we discuss in detail the more difficult modeling issues and reactions with non-standard kinetics.
Table 2 gives the assumed values of volumes, transport parameters, and hepatocyte parameters. Table 3 gives the parameter choices and references for biochemical reactions.
The differential equations for the variables listed in Table 1 are:. APAP is absorbed from the gut into the portal circulation which flows into the liver. In our model, our oral doses are deposited in the gut compartment and then removed and put into the liver with linear kinetics. In[ 11 ] the half life for gastric emptying was calculated to be 7 minutes for oral liquid doses and overnight fasting.
Most of the dose is absorbed in 30 to 60 minutes. The bioavailability of APAP is known to vary considerably depending on age, method of administration, and gut contents. We assume each is Michaelis-Menten and take the K m values from[ 16 ].
Cyp3A4 dominates by having a much larger V max than the other two enzymes. Allosteric activation, including substrate activation, of P enzymes has been extensively documented[ 17 — 19 ]. We have included substrate activation the Hill term on the right and found that if we omitted this substrate activation then the cytochrome oxidase reactions did not produce enough NAPQI at high overdoses. We use a previously published model of liver glutathione metabolism[ 9 ].
NAPQI is believed to exert its toxic effects by binding covalently to liver proteins leading to protein denaturation and necrosis of liver cells[ 6 , 26 , 27 ]. We model the reaction as linear and reversible because covalent binding of NAPQI gradually declines after eight hours[ 28 , 29 ].
The rate at which functional hepatocytes are damaged is proportional to the product of the number of functional hepatocytes and the concentration of covalent binding of NAPQI. We use the differential equations for the rate of change of the number of living hepatic cells and the rate of change of the number of damaged cells from[ 10 ].
There are few measurements of overall transport rates of the metabolites between the compartments of the model. Values of the transport coefficients are given in Table 2. We modeled an oral dose of APAP by setting an initial value in the gut compartment. From the gut compartment, the dose first enters the liver where some of it is metabolized and conjugated, and the rest enters the general circulation from where it is taken up by liver and tissues or excreted in the urine.
The match to the experimental data is excellent. Times courses in the plasma. Panel B shows the values measured in the plasma redrawn from Prescott et al. It is known that high doses of APAP are toxic for two reasons. In Figure 3 , we show model computations of the rates of the glucoronidation reaction, the sulfation reaction and the cytochrome P reaction in the liver at 0. The sulfonation reaction saturates at relatively modest doses, but the rates of the glucoronidation reaction and the rate of formation of NAPQI by the P reaction increase monotonically with dose.
The dramatic increase in the synthesis of NAPQI is seen in Figure 4 where we plot the velocities as a percentage of their value relative to those computed at a standard dose. These elimination rates correspond well with the data in[ 7 ].
Liver reaction velocities as function of dose. Panel A shows the sum of the rates of the glucoronidation reactions in the liver 0. Similarly, Panels B and C show the rates of the sulfation reaction and the sum of the P reactions, respectively.
The sulfation reaction saturates at relatively modest doses. Liver reaction velocities as percent of velocities for a therapeutic dose. Note the steep rise of the P reactions as the dose increases. Accumulation of metabolites in the urine. The results correspond well to those reported in[ 7 ]. We give the dose in moles for easy comparison to the experimental data. Mitchell et al. These model results are shown in Figure 6 A and show a close similarity to the experimental results of[ 6 ] shown in Figure 6 B.
Glutathione depletion and covalent binding. Panel A shows model results. The blue curve shows the liver GSH concentration as a percentage of normal left scale 2 hours after the a dose of APAP as a function of dose size.
The red curve shows the concentration of covalent binding of NAPQI right scale scaled to equal 2 at extremely high doses for easy comparison with the results of Mitchell et al. Panel B shows the comparable experimental results redrawn from[ 6 ] for the same two quantities. The recommended therapeutic dose of APAP is mg not more than four times per day [ 33 , 34 ]. In Australia and new Zealand, the recommended dose is to mg every four to six hours, not to exceed mg per day[ 1 ].
In the USA, the maximum dosage per day recommended by the manufacturer MacNeil Consumer Healthcare was reduced from mg eight mg pills to mg six mg pills in [ 35 ]. Although high doses of APAP are well known to be associated with increased risk of liver failure, chronic exposure to standard therapeutic doses is also not without risk.
Forget et al. Nuttall et al. Watkins et al. This study was stopped early due to the frequency and magnitude of the elevation in ALT in the treatment group relative to controls, although none of the participants expressed symptoms of liver disease.
In a prospective study, Sabate et al. These studies show that chronic usage of APAP at recommended therapeutic levels probably does mild liver damage and may be associated with a reduction in GSH levels that compromise antioxidant defense capacity. We computed the effect of a mg dose every 6 hours for a period of 10 days.
These new dynamic steady states are achieved after about hours. In comparison, Nuttall et al. In Figure 7 C we show an estimate of liver damage done by these chronic doses. The estimate of liver necrosis is rather small, less that 0. The liver necrosis curve oscillates because cells that die during a dose are replaced by regenerated cells; we take the regeneration rate from[ 10 ].
Our model simulations suggest that chronic usage of APAP at recommended therapeutic levels probably does mild liver damage and may be associated with a reduction in GSH levels that compromise antioxidant defense capacity. Glutathione depletion and hepatic necrosis under chronic therapeutic dosing. The curves reach their new steady states after about hours.
The curves oscillate because of the period dosing of APAP, the resynthesis of GSH in the liver, and regeneration of cells in the liver.
The activity of these enzymes is enhanced by a variety of chemicals, including caffeine[ 40 , 41 ] and anticonvulsant drugs[ 42 ], and it is well known that co-ingestion of these drugs with APAP can greatly enhance the toxicity of APAP. A relationship between the consumption of ethanol and the toxicity of APAP has also long been known[ 43 ].
In rats and mice, chronic exposure to alcohol causes an increased expression of CYP-2E1 and increases the activity of the enzyme 5- to 7-fold[ 44 , 45 ]. In humans the effect is much less dramatic, and alcohol consumption causes a transient two-fold induction of CYP-2E1 [ 43 , 46 ]. The role of alcohol in enhancing the toxic effects of APAP is variable and acute alcohol doses may have different effects on P induction than chronic exposure to alcohol[ 43 ].
We used our model to study the effect of increased activity of the P enzymes on the level of NAPQI covalent binding and the predicted associated level of hepatic cell necrosis. Doses of 2 to 4 times the therapeutic dose have only small effects, but the effect increases rapidly with doses above 8 times the normal therapeutic dose if P activity is elevated. Panel A : Model computations show the effect of P activity on liver necrosis at 12 hours after APAP doses of various sizes normal, green; twice normal, blue; four times normal, red.
For relatively modest doses, P activity has little effect in both cases. However, the effect of P activity is dramatic for high doses. Prescott[ 43 ] has suggested that increased APAP toxicity in the presence of alcohol may occur only when the liver is already compromised by other factors.
Our finding that there is only a small increase increase in covalent binding after a therapeutic dose, even with a four-fold increase in CYP P activity supports this idea. There are two reasons to expect that the glucoronosyl tranferase enzymes may be crucial for preventing liver damage. Furthermore, a large number of genetic variants have been described in the UGT genes that are due to mutations in both the coding and regulatory regions of the genes[ 48 — 53 ].
These genetic variants are common and can have profound effects on the APAP glucoronidation capacity of the liver. For instance, Fisher et al. With the normal values given in Methods of V max for the four glucoronosyl tranferases, there is almost no liver damage the black curve in Figure 9.
Polymorphisms in glucoronosyl transferases affect liver damage. The activity of the glucoronosyl tranferases has a dramatic effect on liver damage. With normal parameter values black curve there is almost no hepatocyte death. Since the purpose of NAC rescue is to replenish GSH in the liver, it is important to know the time course of GSH in reponse to various doses and how quickly it recovers.
Because our acetaminophen model is connected to our GSH model we can compute these time courses explicitly. Figure 10 shows the time-line of decline and recovery of hepatic GSH after a therapeutic dose 1 g , and after 5 g, 10 g, 15 g, and 20 g doses, respectively.
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