Therapeutic Doses Of Paracetamol Research Articles

Paracetamol as a basic component of a modern approach to adequate perioperative analgesia

The problem of adequate perioperative anesthesia is one of the most pressing in the current health care system, given its medical, humanistic and socio-economic aspects. Currently, the standard of postoperative analgesia is multimodal analgesia (MMA). One of the major and required components of MMA is paracetamol, which has antipyretic and analgesic effects with limited peripheral anti-inflammatory activity. Most authors consider intravenous paracetamol as a base drug in a multimodal analgesia strategy for a variety of surgical interventions, which reduces the need for opioids and reduces the side effects of the latter, which in turn significantly affects the results of treatment and the length of hospital stay.Numerous studies in many countries have created a broad evidence base for the clinical use of this drug. Due to its pharmacokinetic and pharmacodynamic properties, it has been shown that intravenous paracetamol has several advantages over oral and rectal forms: early and more effective onset of analgesia and stable maintenance of the therapeutic dose of paracetamol are explained by the formation of a faster and higher peak in the concentration of the drug. The side effects of using paracetamol can be compared with placebo. The mechanism of action of the drug is different from the mechanism of action of NSAIDs, however, is still not fully understood. It may possibly involve inhibition of cyclooxygenase, cannabinoid, or nitric oxide pathways in the central nervous system. Intravenous paracetamol is a safe and effective first-line drug for the treatment of moderate pain in the perioperative period.

Successful Outcome Following a Loading Dose of N-Acetylcysteine to Treat Hepatotoxicity after Repeated Therapeutic Doses of Paracetamol

We describe a case of liver failure in a child with repeated therapeutic doeses of paracetamol after being given multiple doses to manage pyrexia during a viral illness. The child was treated successfully with only a single loading dose of N-acetylcysteine. This case highlights the importance of parental advice and physician vigilance in preventing hepatotoxicity paracetamol overdose during viral illnesses.

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

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

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study

Retrospective accounts suggest that therapeutic doses of paracetamol can produce severe hepatic injury in patients with putative high-risk conditions, including alcoholism and infectious hepatitis. Metabolism of paracetamol to its hepatotoxic metabolite is enhanced in patients who abuse alcohol, who also have compromised liver defences from depressed hepatic glutathione. To determine the effect of paracetamol on serum liver tests of newly abstinent subjects who abuse alcohol, including subjects with hepatitis C infection. A randomized, double-blind, placebo-controlled study. Adult alcohol abusers with a current drinking episode longer than 7 days received either placebo or paracetamol 4 g/day for 5 days. Of 142 subjects enrolled, 74 received paracetamol and 68 received placebo. Mean ALT activity during treatment increased from 48 to 62 IU/L in the paracetamol group and from 47 to 49 IU/L in the placebo group. Maximum ALT was 238 and 249 IU/L in the paracetamol and control groups respectively. The INR remained unchanged and serum bilirubin decreased in both groups. Subgroup analyses for subjects with alcoholic hepatitis, hepatitis C virus antibody and other subgroups showed no statistical difference between groups. Administration of paracetamol 4 g/day appears safe in newly abstinent patients who abuse alcohol.

FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?

Hepatotoxicity from paracetamol is of great concern because of the considerable number of patients who develop severe toxicity from this drug. A group of senior medical practitioners, academics and scientists were brought together on June 29 and 30, 2009 by the Food and Drug Administration of USA (FDA) with the aim of providing advice on how to limit the number of cases of hepatotoxicity due to paracetamol in USA. The most contentious recommendations were the reduction in the dose of paracetamol to 650 mg and the elimination of prescription combination products of paracetamol and opiates. The first recommendation indicates that many members of the committee consider, despite much evidence to the contrary, that therapeutic doses of paracetamol (up to 4 g daily) are associated with a significant incidence of hepatotoxicity. The second recommendation, if accepted by FDA, will require major changes in the therapeutic use of paracetamol and opiates. Adoption of these two recommendations may lead to the increased use of NSAIDs with the potential of increasing incidence of NSAIDs-related adverse reactions.

Acute liver failure following therapeutic paracetamol administration in patients with muscular dystrophies

Clinically significant liver damage in patients taking therapeutic doses of paracetamol is very rare. We report two cases of fulminant hepatic failure caused by therapeutic (4 g x day(-1)) paracetamol administration on our Intensive Care Unit. Both patients had a muscular dystrophy and presented with a chest infection on a background of endstage neuromuscular respiratory failure. We also noted one further similar case in the literature and suggest a relationship between muscular dystrophy and paracetamol-induced hepatotoxicity. In this report we discuss in detail possible mechanisms that may account for this apparent association, which include altered pharmacokinetics, reduced glutathione stores, malnutrition and hypoxic injury.

Effects of Therapeutic Dose of Acetaminophen (Paractamol) on Liver Enzymes in Chronic Alcoholics

The effects of therapeutic doses of acetaminophen (paracetamol) on liver enzmes in chronic alcoholics were investigated using 4 groups of 20 subjects each. The results showed that the difference in mean serum bilirubin, AST, ALT and ALP values in indivduals taking therapeutic doses of paracetamol only were significantly increased in both chronic alcoholics not taking paracetamol and chronic alcoholics taking therapeutic doses of paracetamol (P Keywords : Paracetamol. Chronic Alcoholics, Liver Enzymes Journal of Medical Laboratory Sciences Vol. 14 (1) 2005: pp. 23-27

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Therapeutic doses of paracetamol (acetaminophen) are normally considered safe. But in a recent experiment, healthy young volunteers taking therapeutic doses of the drug developed abnormal liver function after only a...

Drug Interactions with Paracetamol

Paracetamol (acetaminophen) is one of the most commonly used analgesic antipyretic drugs worldwide, and it is widely available by prescription and over the counter (OTC). Fortunately, few clinically significant drug interactions have been documented. There is probable potentiation of hepatotoxicity following an overdose from the paracetamol metabolite NAPQI by enzyme-inducing drugs. There is considerable controversy regarding the possible interaction with warfarin in its potential to increase its anticoagulant effects because of discrepancies between observational studies and those in healthy volunteers. Otherwise, no serious adverse drug interactions with therapeutic doses of paracetamol have been confirmed in humans. Because the absorption of paracetamol is so dependent on gastric emptying, other drugs that alter gastric emptying can change its pharmacokinetics; but this would not cause serious adverse effects. Although animal experiments have demonstrated that many compounds can modify paracetamol hepatotoxicity, these are unlikely to be important at therapeutic doses.

Alcohol and paracetamol

Summary There are concerns that therapeutic doses of paracetamol may be hepatotoxic in patients who regularly drink moderate to large amounts of alcohol. Critical examination of case histories reveals that overdoses of paracetamol were responsible for the hepatotoxicity in many cases. Experimental studies in which paracetamol was taken for short periods also show no interaction. Paracetamol is therefore a suitable analgesic for patients who regularly drink moderate to large amounts of alcohol but, as with all patients, care should be taken to minimise the chances of overdose. Key words: acetaminophen, analgesia, hepatotoxicity, liver .(Aust Prescr 2004;27:14–5) Introduction It is well known that overdoses of paracetamol are hepatotoxic. There have been claims that alcohol potentiates this hepatotoxicity to such an extent that therapeutic doses of paracetamol become hepatotoxic in some patients. The so-called ‘alcohol-paracetamol syndrome’ describes the hepatotoxicity which is said to occur from the ingestion of therapeutic doses of paracetamol in moderate to heavy drinkers of alcohol.

Analgesics and Glutathione

A growing body of evidence indicates that glutathione (GSH) plays a vitally important role in cellular function. It detoxifies toxic metabolites of drugs and reactive oxygen species and regulates gene expression, apoptosis, and transmembrane transport of organic solutes. The maintenance of GSH homeostasis is essential for the organism to perform its many functions. The turnover of GSH is a dynamic process, and large quantities of GSH are synthesized per day from its precursor amino acids cysteine, glutamic acid, and glycine. Toxic doses of paracetamol deplete intracellular GSH and result in cell death by a combination of mechanisms, leading to necrosis and apoptosis, mainly in the liver. In clinical situations characterized by low GSH, the risk of toxicity from therapeutic doses of paracetamol may conceivably be increased. This toxicity has been reported in chronic alcoholics who have low intrahepatic GSH and who may have an induced enzyme system that generates the toxic metabolite of paracetamol. Considering the large number of alcoholics in our population and the widespread use of paracetamol, this must be a rare and essentially unpredictable occurrence. Except for anecdotal reports, there is no convincing evidence that other populations in which low GSH has been observed-such as patients with human immunodeficiency virus (HIV) infection or chronic hepatitis C, malnourished patients, and patients with cirrhosis-are at higher risk of experiencing adverse events from paracetamol.

Paracetamol, alcohol and the liver.

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with 'therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol-alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic. The paracetamol-alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol-ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical. In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion-ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.

Evaluation of an Enzyme-Immunometric Assay for Serum α-Glutathione S-Transferase

A commercially available enzyme-immunometric assay for serum alpha-glutathione S-transferase (GST) was evaluated. Endogenous serum alpha-GST diluted linearly within the calibration range. However, we recommend that the sample and second antibody reagent are always added sequentially in the assay to avoid hook effect. Between-assay variability was below 7% across the calibration range and the upper limit of the reference range in adults (n = 219) was 11.4 micrograms/L. Within-individual variability in serum alpha-GST concentrations measured over a 4-6 week period in 4 healthy adults was small. Serum alpha-GST concentrations did not change significantly 6 h after a therapeutic dose of paracetamol. Studies in two patients after liver transplantation showed that serum alpha-GST is a better discriminant of acute changes in liver function than conventional tests. Serum alpha-GST concentrations were unaffected by gross muscle damage, extrahepatic inflammation, or haemolysis and thus appear to be more liver specific than transaminase activities. The effect of renal impairment on serum alpha-GST concentrations requires further investigation.

The effect of therapeutic doses of paracetamol on liver function in the rat perfused liver.

The isolated liver perfusion technique was used to study the effect of therapeutic doses of paracetamol on hepatic gluconeogenesis and bromosulphthalein clearance from the perfusate and biliary excretion of the dye in the rat. Six groups of rats were studied; those in the three experimental groups were given 0.02 g kg-1 paracetamol daily for ninety days. The livers of animals in the control group and in one of the experimental groups were perfused with a medium containing pyruvate. The animals in the second experimental and control group were perfused with a medium containing bromosulphthalein (10 mg/100 mL). The livers of the third experimental and control group were subjected to histological examination. The rate of glucose formation and glucose concentrations were decreased, while, lactate levels and lactate: pyruvate ratios were increased in paracetamol-treated rats. The mean concentration of bromosulphthalein in the perfusate and biliary excretion of the dye were decreased. Macro and micro vesicular fatty change was present in the livers of paracetamol-treated rats. This study demonstrates that chronic administration of therapeutic doses of paracetamol to rats adversely affects liver function, as evidenced by impaired gluconeogenesis and bromosulphthalein clearance from the perfusate, and excretion of the dye into the bile, and provides histological evidence of hepatic damage in rats.

Increased frequency of sister-chromatid exchange and chromatid breaks in lymphocytes after treatment of human volunteers with therapeutic doses of paracetamol

Paracetamol was given to 10 healthy human volunteers in 3 doses of 1 g each during a period of 8 h. Blood samples for lymphocyte cultures were taken before and 24 h after paracetamol administration. A small but significant increase was found in the frequency of sister-chromatid exchanges (SCE) after intake of paracetamol (0.187 ± 0.030 per chromosome before and 0.208 ± 0.024 per chromosome after). After exposure the mean frequency of chromatid breaks per 100 cells was significantly increased (2.16 ± 1.33 versus 0.33 ± 0.50 before exposure). Exposure of human lymphocytes in vitro showed that concentrations of paracetamol above 0.1 mM induced inhibition of replicative DNA synthesis. Increased SCE was found in lymphocytes exposed to 1–10 mM paracetamol for 2 h. Furthermore, 0.75–1.5 mM paracetamol exposure for 24 h increased the frequency of chromatid and chromosome breaks in the lymphocytes. The paracetamol-induced SCE and chromosome aberrations may be secondary effects of paracetamol-induced inhibition of DNA synthesis or due to covalent binding of paracetamol metabolite(s) to DNA.

Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert's syndrome.

A group of eleven subjects with Gilbert's syndrome was characterized by conventional tests and determination of bilirubin and its conjugates in plasma by alkaline methanolysis and thin layer chromatography. After a 1 g dose of paracetamol h.s. the drug and its metabolites were measured by high performance liquid chromatography (HPLC) in the overnight 8-h urine sample. The amounts of paracetamol and of its metabolites recovered in urine were almost identical with those found in the control group (n = 10). The glucuronide:paracetamol ratio, which is considered to be an index of glucuronidation, was not correlated with the fraction of bilirubin present in plasma as glucuronides. These data do not suggest that in subjects with Gilbert's syndrome therapeutic doses of paracetamol are associated with an increased risk for hepatic or systemic toxicity.

Isolation and identification of paracetamol metabolites.

A comparison has been made of the urinary metabolites of volunteers who had taken therapeutic doses of paracetamol with those of persons who had taken an overdose in an attempt to highlight the metabolic changes associated with massive doses. The main technique for examining urine samples was two-dimensional thin layer chromatography. Other chromatographic techniques were used for the isolation and purification of metabolites. The urinary metabolites after a therapeutic dose of paracetamol were identified as free paracetamol, paracetamol sulphate, 3-hydroxy-paracetamol-3-sulphate, 3-methoxy-paracetamol sulphate, paracetamol glucuronide, 3-methoxy-paracetamol glucuronide, paracetamol 3-cysteine conjugate and paracetamol 3-mercapturate. The same metabolites were also present in urine following overdosage but the proportions were quite different. There was particularly a big increase in the relative amounts of cysteine and mercapturic acid conjugates excreted. No new metabolites were found. The significance of these findings is briefly discussed in relation to the metabolism and toxicology of paracetamol.