Paracetamol poisoning in adults

Module overview

Paracetamol is a low cost, effective analgesic that is widely available in the UK. Paracetamol is the drug most commonly taken in overdose and can lead to acute liver failure, which can be fatal. This module focuses on the assessment and management of paracetamol poisoning in adults. It includes current UK guidelines on paracetamol poisoning, which changed in September 2012 following a review by the Commission on Human Medicines. It also discusses strategies to reduce incidence and severity of paracetamol poisoning, and outlines the metabolism of paracetamol at therapeutic doses and in overdose.

Keywords

drug misuse, mental health, overdose, paracetamol overdose, substance misuse

Aims

This module aims to provide an overview of the assessment and management of paracetamol poisoning.

Intended learning outcomes

After reading this module and completing the time out activities, you should be able to:

• Understand the use and metabolism of paracetamol.
• Describe the nature of paracetamol overdose.
• Identify effects of paracetamol poisoning.
• Outline the management of patients with paracetamol poisoning.

Introduction

Paracetamol is a low cost, effective analgesic that is widely prescribed, and is also available to purchase from pharmacies and retail outlets in the UK. Paracetamol is available as a single oral agent in tablet, caplet, capsule, dispersible, suspension and intravenous forms. It is also available in combination preparations in the form of decongestants and other analgesics such as codeine.

The wide availability of paracetamol makes it the product most commonly ingested in overdose in the UK, accounting for more than 40% of all poison-related admissions to hospital (Prescott et al 2009). Most of these incidents are the result of deliberate ingestion, but some may be caused by accidental overdose in an attempt to treat pain or fever.

Paracetamol is safe when taken in the recommended dose of 500mg to 1g (one to two tablets) every four to six hours (a maximum daily dose of 4g (eight tablets) for an adult) (British National Formulary (BNF) 2015/2016). However, if this dose is exceeded, paracetamol can cause toxicity; paracetamol overdose is the leading cause of acute liver failure in the UK (Marudanayagam et al2009). Paracetamol overdose can be treated successfully provided patients are assessed early and receive prompt treatment with the antidote acetylcysteine.

Although healthcare professionals have extensive experience of assessment and management of patients with paracetamol poisoning, many concerns and challenges remain. A particular concern is when to commence antidotal therapy, especially following delayed and staggered presentations (Thanacoody et al 2008). Most enquiries to the National Poisons Information Service (NPIS) relate to paracetamol poisoning (NPIS 2011).

Nurses in many settings will encounter patients who have taken a paracetamol overdose. An understanding of how best to manage these patients will ensure nurses working in the community setting are aware of the importance of early transfer to hospital. Nurses working in hospital departments will be in a position to ensure accurate and timely assessment and management of patients.

Learning Points 

1. The wide availability of paracetamol makes it the product most commonly ingested in overdose in the UK, accounting for more than 40% of all poison-related admissions to hospital, most of these incidents are the result of deliberate ingestion, but some may be caused by accidental overdose in an attempt to treat pain or fever.
2. Paracetamol is safe when taken in the recommended dose of 500mg to 1g (one to two tablets) every four to six hours (a maximum daily dose of 4g - eight tablets for an adult). If the dose of paracetamol is exceeded, it can cause toxicity, leading to acute liver failure.
3. Although healthcare professionals have extensive experience of assessment and management of patients with paracetamol poisoning, many concerns and challenges remain. A particular concern is when to commence antidotal therapy, especially following delayed and staggered presentations

Pharmacology of paracetamol

Paracetamol is an analgesic and antipyretic with relatively few anti-inflammatory or antiplatelet properties. The mode of action is not understood fully, but it is thought that paracetamol acts by inhibiting prostaglandin synthesis in the central nervous system, blocking pain impulse generation and reducing fever (Chandrasekharan et al 2002).

Metabolism of paracetamol

Following oral ingestion of a therapeutic dose of paracetamol, there is rapid absorption from the small intestine, with peak plasma concentrations achieved in 30 minutes to two hours (Nelson et al 2011). This is followed by metabolism in the liver, with 80-90% of the paracetamol undergoing hepatic conjugation (glucuronidation and sulphation) to form non-toxic products (glucuronide and sulphate conjugates), which are excreted by the kidneys (Figure 1) (Nelson et al 2011).

Figure 1 - Paracetamol Metabolism

Learning Points

1. Paracetamol is an analgesic and antipyretic with relatively few anti-inflammatory or antiplatelet properties. It is thought to act by inhibiting prostaglandin synthesis in the central nervous system.
2. Following paracetamol overdose, absorption may be slower and peak plasma concentration is generally achieved within four hours. The non-toxic glucuronide and sulphate pathways become saturated, more paracetamol is oxidised by the cytochrome P450 enzymes and increased amounts of toxic NAPQI are produced.
3. A small amount of paracetamol is excreted in the urine unchanged and the remainder is oxidised by hepatic cytochrome P450 enzymes to form the highly toxic metabolite NAPQI. NAPQI combines with glutathione, an amino acid antioxidant, and is quickly converted to the non-toxic compounds mercapturate and cysteine conjugates. These are eliminated in the urine.
4. In overdose, more paracetamol is oxidised to NAPQI and glutathione reserves become exhausted, NAPQI binds to liver cells and causes liver injury and, in severe cases, acute liver failure and death.

Signs and symptoms of toxicity

The clinical course of paracetamol toxicity may be considered in four stages (Nelson et al 2011), not all of which necessarily occur.

Stage one

Stage one occurs within 24 hours of ingestion and clinical symptoms are non-specific. They may include nausea and vomiting, however many patients will be asymptomatic. Even patients who subsequently develop liver failure can experience few symptoms initially because hepatic injury has not yet occurred and liver function tests (LFTs) are normal (Nelson et al 2011).

Stage two

Stage two occurs between 24 hours and 72 hours after ingestion. With appropriate therapy, this occurs in fewer than 5% of patients presenting with paracetamol overdose (Nelson et al 2011). This stage represents the onset of liver injury and alters LFTs. The most sensitive measure to detect the onset of hepatotoxicity is elevation of alanine aminotransferase (ALT), which is evident before signs of change in liver metabolic function (raised international normalised ratio (INR), elevated bilirubin concentration, hypoglycaemia and metabolic acidosis) are apparent.

Definition

Paracetamol-induced hepatotoxicity is generally defined as ALT concentration above 1,000IU/L. Signs and symptoms vary with severity of liver injury, but patients often experience right upper quadrant pain and tenderness (Nelson et al 2011).

Stage three

Stage three usually occurs between three and five days after overdose, when hepatic necrosis leads to fulminant hepatic failure with encephalopathy, coma and coagulation disorders. ALT concentrations can rise to more than 10,000IU/L. Renal failure is common and is a poor prognostic sign (Pakravan et al 2009). Death is caused most commonly by complications of multi-organ failure (Nelson et al2011).

Stage four

Stage four is defined as the recovery stage and occurs if the patient survives the third stage. Liver and kidney function gradually return to normal over the following weeks (Nelson et al 2011).

Having knowledge of the stages of paracetamol toxicity will assist nurses to identify onset of liver injury and understand the importance of blood sampling to monitor progression of the condition.

Learning Points

1. The clinical course of paracetamol toxicity are explained in four stages. Stage one occurs within 24 hours of ingestion and clinical symptoms are non-specific, such as nausea and vomiting, however many patients will be asymptomatic.
2. Stage two occurs between 24 hours and 72 hours after ingestion. Paracetamol-induced hepatotoxicity is generally defined as ALT concentration above 1,000IU/L. Signs and symptoms vary with severity of liver injury, but patients often experience right upper quadrant pain and tenderness.
3. Stage three usually occurs between three and five days after overdose, when hepatic necrosis leads to fulminant hepatic failure with encephalopathy, coma and coagulation disorders. Renal failure is common and is a poor prognostic sign. Death is caused most commonly by complications of multi-organ failure.
4. Stage four, the recovery stage, occurs if the patient survives. Liver and kidney function gradually return to normal over the following weeks.
5. Nurses should have the knowledge of the stages of paracetamol toxicity so they can identify onset of liver injury and understand the importance of blood sampling to monitor the condition.

Preventing and reducing incidence of paracetamol poisoning

Attempts have been made to lower the incidence and reduce the severity of paracetamol poisoning. Total prevention of impulsive overdose would be impossible because paracetamol is so widely available. Complete withdrawal of paracetamol from the market would deprive the general population of a low cost, safe and effective analgesic, associated with few side effects if taken correctly.

Paracetamol is taken by many people, and the majority never overdose. In addition, alternative pain-relieving medicines such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids may be associated with more side effects, including gastrointestinal disturbances, in therapeutic use. Other pain-relieving medicines are more toxic in overdose – NSAID toxicity can result in acute kidney injury and opioid toxicity can cause respiratory depression.

Nurses are ideally placed to educate patients about the many products that contain paracetamol, recommended dose and dangers associated with taking too many tablets. It has been suggested that incidence of paracetamol overdose could be reduced if the product was labelled as prescription only (Sheen et al 2002). However, this strategy would be an inconvenience to the occasional paracetamol user and would likely increase the workload of GPs, therefore increasing costs to the NHS.

Legislation was introduced to the UK in September 1998 to limit paracetamol sales in an attempt to reduce morbidity and mortality associated with overdose (HM Government 1997). Pack sizes were reduced and over-the-counter sales were restricted to a maximum of 32 tablets from a pharmacy and 16 tablets from other retail outlets. The rationale was to reduce the number of tablets available in the household that could be ingested impulsively.

In addition, paracetamol was supplied in blister packs rather than bottles. This was to prolong the time taken to ingest a large dose and, therefore, give patients more time to reflect on their actions. Changes in pack labelling about the dangers of overdose were also introduced. Following the change in legislation, studies were carried out to examine mortality and liver failure rates, severity of poisoning, hospital admissions and paracetamol sales. There was inconclusive evidence to confirm whether the legislation was successful (Hawkins et al 2007).

An alternative approach to reduce the risk of toxicity associated with paracetamol overdose was to combine methionine with paracetamol (co-methiamol). Methionine converts to glutathione and has a protective function if taken with paracetamol in overdose. However, most overdoses are impulsive, so for this approach to be effective, methionine would need to be added to every paracetamol preparation. As well as the extra cost, this would expose the regular paracetamol user to a product that is unpalatable, has potential side effects and for which long-term use has not been evaluated fully.

Since prevention strategies are difficult to implement and have failed to demonstrate success, healthcare professionals need to ensure guidelines to reduce the risk of morbidity and mortality from paracetamol poisoning are promoted.

Learning Points

1. Alternatives such as NSAIDs and opioids may be associated with more side effects, including gastrointestinal disturbances, in therapeutic use and are more toxic in overdose. NSAID toxicity can result in acute kidney injury and opioid toxicity can cause respiratory depression.
2. Legislation was introduced to the UK in September 1998 to limit paracetamol sales in an attempt to reduce morbidity and mortality associated with overdose. Pack sizes were reduced and over-the-counter sales were restricted to a maximum of 32 tablets from a pharmacy and 16 tablets from other retail outlets. Changes in pack labelling about the dangers of overdose were also introduced.
3. An alternative approach to reduce the risk of toxicity associated with paracetamol overdose was to combine methionine with paracetamol (co-methiamol). Methionine converts to glutathione and has a protective function if taken with paracetamol in overdose. However, most overdoses are impulsive, so for this approach to be effective, methionine would need to be added to every paracetamol preparation.
4. Since prevention strategies are difficult to implement and have failed to demonstrate success, healthcare professionals need to ensure guidelines to reduce the risk of morbidity and mortality from paracetamol poisoning are promoted.