Understanding lactic acidosis in paracetamol (acetaminophen) poisoning

Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure.     

Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration

Summary Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352±40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63±0.02 after 500 mg, to 0.89±0.04 and 0.87±0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.     

Current concepts of the actions of paracetamol (acetaminophen) and NSAIDs

There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is commonly stated that, unlike the non-steroidal anti-inflammatory drugs (NSAIDs), it is a weak inhibitor of the synthesis of prostaglandins. This conclusion is made largely from studies in which the synthesis of prostaglandins was measured in homogenized tissues. However, in several cellular systems, paracetamol is an inhibitor of the synthesis of prostaglandins with IC₅₀ values ranging from approximately 4 μM to 200 μM. Paracetamol is not bound significantly to plasma proteins and therefore the concentrations in plasma can be equated directly with those used in in vitro experiments. After oral doses of 1 g, the peak plasma concentrations of paracetamol are approximately 100 μM and the plasma concentrations are therefore in the range where marked inhibition of the synthesis of prostaglandins should occur in some cells. Paracetamol is metabolized by the peroxidase component of prostaglandin H synthase but the relationship of this to inhibition of the cyclooxygenase or peroxidase activities of the enzyme is unclear. Paracetamol is also metabolized by several other peroxidases, including myeloperoxidase, the enzyme in neutrophils which is responsible for the production of hypochlorous acid (HOCl). The metabolism of paracetamol by myeloperoxidase leads to the decreased total production of HOC1 by both intact neutrophils and isolated myeloperoxidase, even though the initial rate of production of HOC1 is increased. The IC₅₀ value, derived from inhibition of the total production of HOC1 by isolated myeloperoxidase, is 81 μM. Several NSAIDs inhibit functions of neutrophils in media containing low concentrations of protein but their effects, in contrast to that of paracetamol, are generally produced only at concentrations greater than those of the unbound drug in plasma during treatment with the NSAIDs. However, neutrophils isolated during treatment with NSAIDs, such as piroxicam, ibuprofen and indomethacin show decreased function. Paracetamol has little or no anti-inflammatory activity by itself but may potentiate the clinical activity of NSAIDs in the treatment of rheumatoid arthritis.     

Recent developments in the management of paracetamol (acetaminophen) poisoning.

Paracetamol (acetaminophen) poisoning accounts for almost a third of admissions to our district poisons unit, and is the commonest cause of death in such patients. Antidotal treatment may be effective up to 10h after overdose with oral methionine or up to 24h with acetylcysteine (not 15h as previously suggested for the latter). Patients taking paracetamol overdose while also receiving drugs which induce hepatic enzymes are more susceptible to liver damage, and antidotal treatment may be necessary at lower plasma paracetamol concentrations (50% of the normal treatment line). As survival following liver transplantation is now increasing, it is important to identify early prognostic indicators in fulminant hepatic failure, so that those patients with a high chance of fatal outcome can be considered for transplantation. Useful indicators are the presence of acidosis, marked prolongation of prothrombin time or a continued rise in prothrombin time on day 4 after the overdose. There is no evidence that paracetamol or acetylcysteine are teratogenic in pregnancy. Delays in administering acetylcysteine after paracetamol poisoning in pregnancy have been shown to increase the risk of spontaneous abortion and fetal death. Thus, acetylcysteine should be started as early as possible where treatment is indicated.     

Inhibition of prostaglandin synthesis in intact cells by paracetamol (acetaminophen)

Despite its wide use, the mechanism of action of paracetamol (acetaminophen) is uncertain. It is commonly stated to be a weak inhibitor of the synthesis of prostaglandins (PGs) by the prostaglandin H synthases (COX-1 and COX-2) but paracetamol inhibits the synthesis of PGs in stimulated cultured cells with IC₅₀ values ranging from 4 to 200 _M. Paradoxically, it generally stimulates PG production in broken cell preparations. Here we show that paracetamol inhibits the production of PGs in human rheumatoid synoviocytes during stimulation by interleukin1 (0.1ng/ml) for 18 h. Paracetamol inhibited the production of both PGE₂ and PGF₂with median IC₅₀ values of 7.2 and 4.2 _M respectively, without affecting the or the level of the constitutive enzyme, COX-1 or the interleukin-1 mediated induction of both COX-2 and cytosolic phospholipase A₂- (cPLA₂-). These data indicate that paracetamol suppresses delayed PG production by direct modulation of the cPLA₂- /COX-2 pathway at therapeutic concentrations. Paracetamol is a substituted phenol and its effects on the synthesis of PGs are very similar to those of other phenols. Paracetamol should be considered to inhibit the production of PGs although the cause of its selectivity; analgesic and antipyretic effects with weak antiplatelet and anti-inflammatory effects is unknown.     

Effect of acetaminophen (paracetamol) on human osteosarcoma cell line MG63

Aim:

To examine the effects of acetaminophen (paracetamol), a nonsteroidal anti-inflammatory drug (NSAID), on different cellular and functional parameters of the human osteosarcoma cell line MG63.

Methods:

Flow cytometry was used to study proliferation, antigenic profile, and phagocytic activity, and radioimmunoassay was used to determine osteocalcin synthesis as a cell differentiation marker.

Results:

Short-term treatment with therapeutic doses of paracetamol(5 or 25 μmol/L) reduced cell proliferation, osteocalcin synthesis, and phagocyte activity, and increased the expression of antigens involved in antigen presentation to T lymphocytes (CD80, CD86, HLA-DR).

Conclusion:

These findings suggest that paracetamol activates the osteoblast, inducing its immunogenic action to the detriment of its bone formation capacity.     

The effect of thiamine deficiency on the metabolism of acetaminophen (paracetamol)

The effect of thiamine deficiency on the metabolism of acetaminophen (paracetamol) was studied in male and female rats. Deficiency of thiamine enhanced the rate of disappearance of the drug from the plasma which resulted in the apparent decrease in the plasma half-life. The alteration in the rate of acetaminophen metabolism was, in part, due to an increase in the formation of the water soluble metabolites characterized as glucuronide and sulfate conjugates. The effect of thiamine deficiency could be overcome by supplementation with thiamine by intraperitoneal injection. A single large dose of thiamine (650 μg) could reduce the rate to the normal level within 24 hr. However, a series of 5 low doses (260 μg/dose/day) was required to produce the same effect.     

Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose

AIMS: Oral activated charcoal is used to treat drug overdose and is effective at reducing drug absorption when administered within 1 h of drug ingestion. There are fewer data on efficacy when the delay is longer, as is the case in most drug overdoses. This study investigated the efficacy of activated charcoal at preventing paracetamol (acetaminophen) absorption after simulated overdose when administration was delayed between 1 and 4 h. METHODS: An open randomized-order four-way crossover study was performed in healthy volunteers comparing the effect of activated charcoal 50 g on the absorption of 3 g paracetamol tablets when administered after an interval of 1, 2 or 4 h or not at all. Plasma paracetamol concentrations were measured over 9 h after paracetamol ingestion using h.p.l.c. and areas under the curve between 4 and 9 h (AUC(4,9 h)) calculated as a measure of paracetamol absorption. RESULTS: Activated charcoal significantly reduced paracetamol AUC(4,9 h) when administered after 1 h (mean reduction 56%; 95% Confidence intervals 34, 78; P<0.002) or 2 h (22%; 6, 39; P<0.03) but not after 4 h (8%; -8, 24). When administered after 1 h activated charcoal reduced individual plasma paracetamol concentrations significantly at all times between 4 and 9 h after paracetamol administration. Administration at 2 or 4 h had no significant effect. CONCLUSIONS: These results in healthy volunteers cannot be extrapolated directly to poisoned patients. However, they provide no evidence of efficacy for activated charcoal when administered after an interval of more than 2 h.     

The effects of additives on the growth and morphology of paracetamol (acetaminophen) crystals

It is well known that the presence of impurities can dramatically affect the nucleation, morphology, and chemical properties of crystals. Although literature is replete with examples of impurity or additive-induced modifications of crystals, few have examined the interaction of these compounds with distinct growing faces. In this study, we utilize atomic force microscopy (AFM) and scanning electron microscopy (SEM) to investigate the influence of two structurally related additives of paracetamol (acetaminophen) on its crystal morphology. We also probe, in situ, the effects of these additives on the morphology and growth rate of steps on the (0 0 1) face of the crystal. This study, in conjunction with further investigations, aims to establish the specific mechanisms of inhibition of these additives on each face of paracetamol, and provide a means of overcoming the poor compaction behaviour of paracetamol.     

Comparative analgesia, cardiovascular and renal effects of celecoxib, rofecoxib and acetaminophen (paracetamol)

Comparisons are made between the specific COX-2 inhibitors, celecoxib and rofecoxib, and acetaminophen. The specific COX-2 inhibitors are a significant advance in therapy because their anti-inflammatory, analgesic and antipyretic activities are associated with a high degree of gastrointestinal safety. Acetaminophen is often not considered to be a potent inhibitor of COX-2 but it is a potent inhibitor of prostaglandin synthesis in intact cells after stimulation by cytokines. Its weak activity on the pathway of prostanoid synthesis involving COX-1 is shown by its weak anti-platelet activity and good gastrointestinal safety. The specific COX-2 inhibitors and acetaminophen are analgesic after dental surgery, orthopedic surgery and in osteoarthritis although acetaminophen appears to be a slightly weaker agent. The apparent analgesic activity of both the COX-2 inhibitors and acetaminophen may, in part, be due to their anti-inflammatory properties. Both groups of drugs also decrease the urinary excretion of prostacyclin metabolites consistent with inhibition of the systemic and renal activity of the COX-2 system. During repeated dosage with the specific COX-2 inhibitors, the 24 hour urinary excretion of sodium is only inhibited for the first day of treatment while the excretion of sodium is still decreased over the first 3 hours after the individual doses. Therapeutic doses of the COX-2 inhibitors and overdoses of acetaminophen have been associated with the development of occasional cases of acute renal failure. Acetaminophen also may decrease the excretion of sodium and the reason for its greater renal safety at therapeutic doses is unclear. Myocardial infarction has also been attributed to the specific COX-2 inhibitors from meta-analysis of large scale clinical trials and examination of reports of adverse drug reactions although this is still a topic of considerable discussion. No such associations have been made with acetaminophen, possibly because it is a weak inhibitor of COX-1 in platelets.     

Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose

BACKGROUND: The evidence for efficacy of gastric lavage and activated charcoal for gastrointestinal decontamination in poisoning has relied entirely on volunteer studies and/or pharmacokinetic studies and evidence for any clinical benefits or resource savings is lacking. AIM OF STUDY: To investigate the value of gastrointestinal decontamination using gastric lavage and/or activated charcoal in acetaminophen (paracetamol) poisoning. PATIENTS AND METHODS: We analyzed a series of 981 consecutive acetaminophen poisonings. These patients were treated with gastric lavage and activated charcoal, activated charcoal alone, or no gastrointestinal decontamination. The decision as to which treatment was received was determined by patient cooperation, the treating physician, coingested drugs, and time to presentation after the overdose. RESULTS: Of 981 patients admitted over 10 years, 10% (100) had serum concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The risk of toxic concentrations for patients ingesting less than 10 g of acetaminophen was very low. In patients presenting within 24 hours, who had ingested 10 g or more, those who had been given activated charcoal were significantly less likely to have probable or high risk concentrations (Odds ratio 0.36, 95% CI 0.23-0.58, p < 0.0001). Gastric lavage, in addition to activated charcoal, did not further decrease the risk (Odds ratio 1.12, 95% CI 0.57-2.20, p = 0.86). CONCLUSIONS: Toxic concentrations of serum acetaminophen (paracetamol) are uncommon in patients ingesting less than 10 g. In those ingesting more, activated charcoal appears to reduce the number of patients who achieve toxic acetaminophen concentrations and thus may reduce the need for treatment and hospital stay.     

Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol)

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.     

Effects of posture and sleep on the pharmacokinetics of paracetamol (acetaminophen) and its metabolites

The effects of posture and sleep on the pharmacokinetics of paracetamol (acetaminophen) 500 mg and its metabolites were studied in 8 healthy men. The mean residence times for paracetamol or its metabolites were significantly altered by change in posture or by sleep, whereas other pharmacokinetic parameters were unchanged. The change in mean residence time is consistent with a faster absorption of paracetamol during ambulation. The present data suggest that the proposed posture-related changes in volume of distribution do not exist, and that there is no pharmacokinetic basis for a headache being relieved by taking paracetamol and lying down.     

The efficacy of ketoprofen and paracetamol (acetaminophen) in postoperative pain after third molar surgery

1 A placebo-controlled, double-blind, randomized trial was carried out to evaluate the efficacy of single doses of racemic ketoprofen 12.5 and 25  mg and paracetamol 500 and 1000  mg in patients with post-operative pain after third molar surgery over a 6  h investigation period.
2 Outcome variables included overall pain scores (AUC(0,360  min), maximum pain relief, pain relief at 1  h after dosage and the number of patients taking escape analgesics.
3 Overall pain scores (AUC(0,360  min) were significantly lower for all active treatments when compared to placebo ( P <0.01).
4 Both ketoprofen treatments and patients treated with paracetamol 1000  mg reported significantly greater pain relief ( P <0.01) and a later time to taking escape analgesics ( P <0.01) than patients medicated with placebo.
5 At 1  h after dosage, pain scores were significantly less ( P <0.01) after both doses of ketoprofen when compared with placebo.
6 Single doses of ketoprofen 12.5 and 25  mg, together with paracetamol 1000  mg are effective analgesics for treating post-operative pain after third molar surgery. These treatments provide up to 4  h of pain relief after this surgical procedure.     

Effects of acetaminophen (paracetamol) in the embryonic development of zebrafish,Danio rerio

Acetaminophen, or paracetamol is an over‐the‐counter analgesic generally used by all groups of people, including pregnant women. The present investigation aims to elucidate the effects of acetaminophen on the development of zebrafish Danio rerio in which embryogenesis is ex utero. Developing eggs (n = 30) were exposed to different doses (0, 1, 5, 10, 50 and 100 µg L^?1) of the drug in triplicate and observations were made hourly until gastrulation and once in 24 h thereafter for seven consecutive days. Acetaminophen induced anomalies at different levels of development in a dose‐dependent manner, causing impairment in (1) the early development, (2) hatching, (3) organogenesis (by altering the rate of apoptosis), (4) larval growth and morphometry, (5) tail and tail‐fin formation, (6) pigmentation and (7) larval behavior and survival. The results of the present study clearly reveal that acetaminophen interfered with the normal embryonic development, growth, behavior and survival of D. rerio larvae. Copyright © 2009 John Wiley & Sons, Ltd.