Paracetamol

Introduction

Poisoning with paracetamol is common in Australia, as well as other Western countries. In the United States over 100,000 potential paracetamol poisonings are reported annually to the American Association of Poison Control Centers. In the United Kingdom, paracetamol poisoning accounts for over 40% of poisoning exposures presenting to emergency departments.

Pharmacokinetics and pathophysiology

Paracetamol ( N -acetyl para-aminophenol, acetaminophen) is rapidly absorbed from the gastrointestinal (GI) tract in therapeutic doses with peak plasma concentrations occurring within 30 to 60 minutes with immediate-release tablet formulations and less than 30 minutes with liquid preparations. Bioavailability increases with the size of the dose, ranging from 68% following 500 mg to 90% following 1 to 2 g orally. Time to peak plasma concentration may be delayed in the presence of co-ingestants that delay gastric emptying, such as opioids, antihistamines and other anticholinergic agents. The volume of distribution for paracetamol is approximately 1 L/kg, with around 50% plasma protein binding. Metabolism occurs primarily in the liver with small amounts metabolized renally. Metabolites are renally excreted with less than 4% excreted unchanged in the urine. Elimination half-life is approximately 1.5 to 2.5 hour following therapeutic dosing. Paracetamol is metabolized by three mechanisms. With therapeutic dosing, approximately 60% is conjugated to glucuronide metabolites and 35% to sulphate metabolites. Microsomal enzymes metabolize less than 5% of paracetamol. CYP2E1 is the major iso-enzyme but CYP2A and CYP1A2 are also significant. Microsomal metabolism produces a reactive intermediary metabolite, N -acetyl-para-benzoquinoneimine (NAPQI). This is rapidly conjugated with glutathione to produce non-toxic mercapturic acid and cysteine metabolites that are renally excreted. Elimination half-life is the same for adults, children and elderly patients, but may be slightly elevated in neonates.

In overdose, glucuronidation and sulphation pathways are rapidly saturated, resulting in increased metabolism of paracetamol by the microsomal enzyme pathway. From animal studies, when glutathione stores are depleted by more than 70%, NAPQI accumulates in the liver and binds to hepatocytes, resulting in cell death and predominantly centrilobular hepatic necrosis.

Microsomal metabolism of paracetamol may be enhanced by chronic alcohol ingestion or starvation. Inhibition of microsomal metabolism may occur in the presence of acute alcohol ingestion and with the administration of 4-methylpyrazole. Therapeutic doses of cimetidine do not decrease excretion of mercapturate metabolites following therapeutic doses of paracetamol in humans. There are no human studies supporting the use of cimetidine in prevention of hepatotoxicity following paracetamol poisoning.

A modified-release formulation of paracetamol (Panadol Osteo) has been on the market in Australia for the management of arthritis pain since 2002. This formulation contains 665 mg of paracetamol in a bilayer tablet with one-third being immediate-release and two-thirds modified-release. It has been designed to release paracetamol slowly and to maintain a therapeutic concentration for up to 8 hours. Human volunteer data in simulated overdose suggest a delay to, and reduction in, peak paracetamol concentration. Comparison with immediate-release paracetamol at similar doses showed a reduction in peak paracetamol concentration and area under the curve by more than 50%, and a delay to peak paracetamol concentration from 1 to 3 hours. Pharmacokinetic data following deliberate self-poisoning with this formulation suggest that there may be a delay in peak serum concentration, which may go undetected with a single 4-hour serum paracetamol estimation. Panadol Osteo overdose also may be associated with prolonged and biphasic absorption and detectable paracetamol concentrations beyond the duration of the standard 20-hour N -acetylcysteine (NAC) treatment protocol. Massive ingestion of immediate-release paracetamol (>50 g), particularly with co-ingestants that slow GI motility (opioids, antihistamines, anticholinergic agents), also can be associated with delayed peak and prolonged elevation of serum paracetamol concentrations.

An isolated small rise in international normalized ratio (INR) has been observed in patients with paracetamol poisoning in the absence of hepatic impairment. Mild elevations in INR and reduced levels of functional Factor VII are observed in up to 66% of patients with an extrapolated 4-hour paracetamol concentration greater or equal to 1000 μmol/L (150 mg/L). This effect is related to the inhibition of vitamin-K-dependent activation of coagulation factors.

Clinical features

The clinical features of early paracetamol poisoning are non-specific and do not permit diagnosis on clinical grounds. Classically, untreated poisoning progresses through four stages of toxicity. Stage 1 lasts about 24 hours and is a subclinical period where the patient may exhibit only mild nausea, vomiting and malaise. During this period, paracetamol is being metabolized, glutathione stores are being depleted and hepatotoxicity is in its early stages. In severe poisoning, mild elevation of hepatic aminotransferases may be apparent as early as 16 hours post-ingestion. In stage 2, nausea and vomiting resolve. Patients may develop right upper quadrant pain and hepatic tenderness 24 to 48 hours post-ingestion. Liver function begins to deteriorate, with increasing aminotransferases, bilirubin and prothrombin time. Stage 3 is essentially a continuum of the above between 72 and 96 hours post-ingestion. Hepatic function deteriorates and chemical hepatitis, jaundice and encephalopathy may develop. Peak aminotransferases are seen around 72 hours post-ingestion. Stage 4 is either the stage of resolution with a fall in aminotransferase concentrations or (Aspartate transaminase (AST) tends to fall earlier than alanine transaminase (ALT)), less commonly, the development of fulminant hepatic failure. Renal failure may also develop as a consequence of paracetamol toxicity. This may either be independent of hepatotoxicity with direct renal toxicity from renal microsomal enzymatic metabolism of paracetamol to NAPQI or as a consequence of liver failure–induced hepato-renal syndrome.

Mitochondrial dysfunction (coma, lactic acidaemia, hypothermia, hyperglycaemia) may result from massive ingestion of paracetamol. This is independent of any hepatic impairment. Patients may present with a high anion gap metabolic acidosis. Other uncommon manifestations of paracetamol overdose may be acute renal failure or pancreatitis.

In general, most patients recover from paracetamol toxicity. The overall untreated mortality is less than 1% and that of untreated patients with hepatotoxicity is around 3.5%.

Assessment of risk of hepatotoxicity

The risk of hepatotoxicity following acute ingestion of paracetamol is dose dependent. In healthy adults, hepatotoxicity may result from ingestion of more than 200 mg/kg or 10 g, whichever is the least. In children less than 6 years old, ingestion of more than 200 mg/kg may result in toxic serum concentrations. The threshold for toxicity may be less in patients with underlying hepatic impairment (e.g. chronic alcoholic liver disease, chronic active hepatitis), severe malnutrition or in the presence of microsomal enzyme-inducing agents.

The paracetamol-treatment nomogram shows a clear relationship between the serum paracetamol concentration and the potential for subsequent hepatotoxicity following a single ingestion of immediate-release paracetamol. The nomogram begins at 4 hours post-ingestion to allow for the absorption and distribution of paracetamol. Serum concentrations taken less than 4 hours post-ingestion may be unreliable in predicting the potential for hepatotoxicity.

The risk of hepatotoxicity from untreated acute paracetamol ingestion can be estimated from the nomogram. Patients with a serum concentration falling above a line from 1300 μmol/L (200 mg/L) at 4 hours post-ingestion to 170 μmol/L (25 mg/L) at 16 hours post-ingestion (the ‘probable toxicity’ line) will have a 60% chance of developing hepatotoxicity (ALT > 1000 IU/L) if left untreated. This risk increases to 87% in untreated patients with paracetamol concentrations above 2000 μmol/L (300 mg/L) 4 hours post-ingestion. The current ‘treatment line’ in Australasia is the ‘possible hepatotoxicity’ line ( Fig. 25.6.1 ), 1000 μmol/L (150 mg/L) at 4 hours post-ingestion to 125 μmol/L (16 mg/L) at 16 hours post-ingestion. This was adopted to allow for errors in calculation of the time of ingestion, provides an additional margin of safety for patients who may possess risk factors, and removes the need for potentially confusing additional lines. The safety of treatment decisions to commence NAC based upon this 1000 μmol/L (150 mg/L) at 4 hours nomogram line has been demonstrated in the United States in over 11,000 patients, where no patients treated with NAC within 15 hours of ingestion died. In contrast, the use of the higher line (1300 μmol/L at 4 hours) has been associated with cases of patients with a serum paracetamol concentration below this line that subsequently developed acute hepatic failure or suffered a fatal outcome.

Repeated supratherapeutic dosing with paracetamol is associated with an increased risk of hepatotoxicity, particularly in those with the hepatic risk factors. Liver failure has been reported in retrospective case series with chronic use of as little as 4 g a day in patients with underlying acute illnesses with associated decreased oral intake. However, prospective evaluation of the risk of liver failure with therapeutic doses of paracetamol in chronic alcoholics does not suggest an increased susceptibility to liver failure in this subset of patients. It is important to note that the paracetamol-treatment nomogram is not useful in the assessment of hepatotoxic risk in these patients. In alcoholic patients, markedly raised hepatic aminotransferases (>1000 IU/L) suggest a toxin-induced hepatitis, as seen with paracetamol. Both alcoholic hepatitis and viral hepatitis rarely produce aminotransferase concentrations that are above 1000 IU/L.