Good ol’ paracetamol: ‘But an overconsumption takes its toll’

Authors Sher Mohammad and others discuss one of the most frequently used medicines around the world

Brief History of Paracetamol/Acetaminophen

In the 1880s, two young doctors at the University of Strasburg, to eradicate worms, by mistake dispensed acetanilide to a patient instead of naphthalene. They noticed that the drug had a small impact on intestinal parasites, however, it significantly decreased high temperature. Young doctors, Arnold Cahn and Paul Heppa, quickly published their discovery and acetanilide was introduced into medical practice in 1886 under the name antifebrin. Soon it appeared that although the production of the drug was very cheap, acetanilide could not be used as an antipyretic medicament due to its high toxicity, the most alarming was met-hemoglobinemia. A few years later, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored.

Phenacetin was introduced as antipyretic in 1887. Six years later, paracetamol was discovered in the urine of individuals who had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. So, a major portion of a dose of phenacetin would be rapidly metabolised to paracetamol, it seemed possible that phenacetin owed some of its antipyretic activity to its main metabolite, paracetamol, whereas its most troublesome side effect (methemoglobinemia) was due to another metabolite-phenetidine. So, phenacetin was discontinued as antipyretic.

It was obvious that paracetamol could be derived from the above-mentioned chemicals, but by this time, paracetamol had already been synthesized by Harmon Northrop Morse [1] via the reduction of p-nitrophenol with Tin in glacial acetic acid.

 

p-nitrophenol + acetic acid Sn N-acetyl-p-aminophenol

 

While this synthesis was first performed in 1873, paracetamol was not used medically for another two decades. N-acetyl-p-aminophenol appeared to be the most satisfying compound, which was introduced for limited use in 1893, and for wide unrestricted use after 1950s.

Both paracetamol and acetaminophen are contractions of the chemical names for the compound. The word” paracetamol” is a shortened form of para-acetyl-aminophenol, and was coined by Frederick Stearns & Co in 1956. While the word” acetaminophen” is a shortened form of N-acetyl-p-aminophenol (APAP), and was coined and first marketed by McNeil Laboratories in 1955.The initialism APAP is used by dispensing pharmacists in the United States. So, there is no difference between acetaminophen and paracetamol, they are both generic names for a chemical substance known as N-acetyl-p-amino-phenol.

Paracetamol is the British and Australian Approved Name as well as the international non-proprietary name used by WHO and in many other countries; acetaminophen is the US adopted name and Japanese accepted name, and the name generally used in Canada, Venezuela, Colombia and Iran.

Paracetamol is one of the most frequently used medicine around the world. Today, paracetamol is used by patients of practically all ages and for indications and is available over the counter. Such wide utilization is primarily due to its proven antipyretic and analgesic actions.

 

Pharmacology of ACETAMINOPHEN

Paracetamol is well absorbed from the gut and readily inactivated in the liver by conjugation to its glucuronide and (to a lesser degree) sulphate. Any fraction that is not conjugated, then undergoes CYP 450 metabolic pathway being converted to cytotoxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI).

 

Table-1: Pharmacology of ACETAMINOPHEN

Risk factors for paracetamol toxicity

Paracetamol poisoning can occur accidentally or as an attempt to die by suicide. Risk factors for toxicity are briefly mentioned here.

 

Table-2: Risk factors for toxicity of Paracetamol

Mechanism of toxicity

Acetaminophen has been postulated to cause liver injury by mechanisms including glutathione depletion, oxidative stress and mitochondrial dysfunction leading to loss of ATP. Factors that induce cytochrome P-450, such as alcohol consumption and possibly,

malnutrition, increase NAPQI synthesis and contribute to glutathione depletion, enhancing paracetamol related toxicity [3,4,5].

 

Toxicokinetics of Paracetamol

1. When taken in normal therapeutic doses, it is mostly converted to nontoxic metabolites via metabolism by glucuronidation and sulphation with a small portion being oxidised via CYP450 enzyme system.
2. CYP450 2E1 and 3A4 convert approximately 5% paracetamol to a highly reactive intermediary metabolite N-acetyl-p-benzoquinone imine (NAPQI).
3. Under normal conditions NAPQI is metabolised by conjugation with glutathione to form cysteine and mercapturic acid conjugates.
4. In case of overdose, the sulphate and glucuronide pathways become saturated, and more paracetamol is shunted to CYP450 system to produce NAPQI. As a result, hepatic glutathione becomes depleted while the demand for glutathione is increased.
5. NAPQI therefore remains in its toxic form in the liver and reacts with cellular membrane (proteins and nucleic acids), resulting in widespread hepatocyte damage and death, leading to acute liver necrosis.

 

Toxicity in animals

Paracetamol is lethal to snakes and has been suggested as a chemical control programme for invasive brown tree snakes in Island of Guam. Doses of 80 mg are inserted into dead mice that are scattered by helicopter as lethal bait to be consumed by the snakes.

Paracetamol is extremely toxic to cats, which lack the necessary UGT 1A6 enzymes to detoxify it. Unlike an overdose in humans, liver damage is rarely the cause of death, instead, methaemoglobin formation and the production of Heinz bodies in RBCs inhibit oxygen transport by the blood, causing asphyxiation (methaemoglobinaemia and haemolytic anaemia). Treatment with N-acetylcysteine recommended.

 

The NPIS-UK advice

The recommended therapeutic dose of paracetamol depends on age. In adults, the maximum dose in 24 hours is 4 gm [6].

Bear in mind that patients with bodyweight <50 Kg are at increased risk of toxicity and overdose at therapeutic doses; oral and intravenous doses should be adjusted in these patients

[7] British Hepatology Pharmacy Group: Prescribing weight-adjusted oral paracetamol in adults.

The National Poison Information Service (NPIS) in the UK defines different types of paracetamol overdoses as follows [8]

a) Acute overdose: excessive amounts of paracetamol ingested over a period of less than one hour; usually in context of self -harm

b) Staggered overdose: excessive amounts of paracetamol ingested over longer than one hour; usually in the context of self-harm

c) Therapeutic excess:

1. Excessive paracetamol taken with intent to treat pain or fever and without self-harm intent
2. Paracetamol ingested at a dose greater than the licensed daily dose AND>75 mg/kg/24 hours
3. Can involve use of excessive dose of the same paracetamol product or inadvertent use of more than one paracetamol-containing product at the same time

 

Paracetamol (acetaminophen) poisoning in humans

While paracetamol is a safe drug in normal doses, it is hepatotoxic and potentially fatal in overdose. In 1966, the first cases of paracetamol poisoning were reported in British Medical Journal. The reports were particularly noteworthy as a major feature was liver failure (BMJ) [9].

How do the patients with Acetaminophen overdose present?

Many patients who present do so within a few hours of taking an overdose, when symptoms and signs are absent or confined to nausea and vomiting. Lactic acidosis and coma can, exceptionally, occur soon after ingestion of massive amounts of paracetamol. Their presence usually implies mixed overdose. Right upper quadrant tenderness is common in patients presenting with established liver damage. Patients who present after 24 hours may already have signs of liver failure-hepatic tenderness, jaundice, impaired consciousness, asterixis, foetor hepaticus, and haemorrhage. Overt liver failure can, however, be delayed for two to three days [10].

 

Table-3: Succinct summary of ACETAMINOPHEN poisoning in humans

Management of paracetamol poisoning

1. Stabilisation with IV fluids and monitoring BP, ECG and urine output in a managed ward.
2. Gastric Decontamination:
   Oral activated charcoal avidly adsorbs acetaminophen and may be administered if the patient presents within one hour after the ingestion of toxic dose. The patient must be awake with protected airway when it is used.
   If the patient has taken a drug which could delay the gastric emptying, then activated charcoal can be given even at a later stage.
3. N-acetylcysteine administration
   Intravenous N-acetylcysteine is the antidote to treat paracetamol overdose and is virtually 100% effective in preventing liver damage when given within 8 hours of the overdose.
   Determine the need for acetylcysteine by plotting the measured paracetamol level (mg/L or µg/ml) against the time since ingestion. If plasma level falls above the line, then give acetylcysteine as per protocol.
   Likewise, if ALT/INR is newly abnormal, consider acetylcysteine irrespective of plasma levels.

The treatment nomogram, originally derived from a study of just 32 patients, separates those who will develop serious hepatotoxicity (transaminase activity >1000 U/L) from those who will not, based on graph of paracetamol concentration against time from ingestion as it falls from 200mg/L at four hours (the “200” line). Medics can consult their poison information service (UK and Ireland: www.toxbase.org/) for treatment recommendations [11].

In the US, Australia and New Zealand a similar semi-logarithmic plot at paracetamol concentration 25% lower (the “150” line) is used to permit a wider margin of error. Some patients reportedly come to harm even if the paracetamol concentration falls below 200 or 150 lines [12.13]

Acetaminophen associated hepatocellular necrosis
Image credit: Courtesy of PathologyOutlines.com, contributed by Anthony W.H. Chan, M.B.Ch.B.

 

The nomogram becomes less reliable after 15 hours.

If the overdose is staggered (ingested over >1 hour), then the nomogram is unreliable.

Loading dose :150 mg/kg; mix in 200 ml of 5% dextrose and infused in one hour
50mg/kg in 500 ml of 5% dextrose over 4 hours
100mg/kg in 1000 ml of 5% dextrose over 16 hours.

Hepatotoxicity is extremely rare in patients treated with acetylcysteine within 8 hours of an acute paracetamol overdose. The efficacy of acetylcysteine decreases after the first 8 hours following an acute paracetamol overdose, with a corresponding stepwise increase in hepatotoxicity with increasing treatment delays between 8 and 16 hours.

Anaphylaxis to acetylcysteine is rare. Hypersensitivity reactions are directly proportional to serum acetylcysteine level and commonly happens during the 1st infusion. It can cause bronchospasm, nausea, flushing and QTc interval prolongation.

 

4. Liver Transplant

(King’s College Hospital Criteria for Liver Transplant: any one of the following)

1. Arterial pH<7.3 after fluid resuscitation and >24 hours since paracetamol ingestion
2. Lactate>3.5 following resuscitation for 4 hours or >3 after fluid resuscitation for 12 hours
3. All three of the following in a 24-hour period
   a. INR>6.5(PT>100 sec)
   b. Creatinine>300µmol/L (>3.4 mg/dL)
   c. Grade 3 or 4 hepatic encephalopathy

 

Conclusion

Paracetamol-induced liver failure is a rare but serious condition. Early intervention with N-acetylcysteine (NAC), neuroprotection, and ammonia clearance is crucial for improving outcomes. Early critical care admission and prompt discussion with transplant centres are essential. While transplant-free survival is improving with better medical management, deciding who truly requires liver transplantation has become more complex due to the growing success of intensive care and NAC therapy. The focus is now on balancing early treatment, proper resource use, and patient selection for transplantation.

 

Conflicts of interest: none declared

 

References

1. Morse,H.N (1878)”Ueber eine neue Darstellungsmethode der Acetylamidophenole[on a new method of preparing acetylamidophenol].Berichte der deutschen chemischen Gesellschaft.11(1):232-233.doi:10.1002/cber.18780110151
2. Ayoub SS, Botting RM, Goorha S, et al Acetaminophen-induced hypothermia in mice is mediated by prostaglandin endoperoxide synthase 1 gene-derived protein.Proc Natl Acad Sci USA.2004;101:11165-11169
3. Schilling A, Corey R, Leonard M, Eghtesad B.Acetaminophen:old drug, new warnings. Cleve Clin J Med.2010;7791):19-27.doi 10.3949/ccjm.77a.09084
4. McClain CJ, Price S,Barve S,Devalarja R,Shedlofsky S.Acetaminophen hepatotoxicity: An update. Curr Gastroenterol Rep.1999;(1):42-49.doi:10.1007/s11894-999-0086-3
5. Sabate M,Ibanez L, Perez E,Vidal X,Buti M,Xiol X,Mas A,Guarner C,Forne M,Sola R, Castellote J,Rigau J,Laporte JR.Paracetamol in therapeutic dosages and acute liver injury: Causality assessment in a prospective case series.BMC Gastroenterol.2011;11:80.doi
6. Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning.BMJ.2011 April 19;342:d2218
7. Healthcare Safety Investigation Branch. Unintentional paracetamol overdose in adults inpatients with low body weight. Feb 2022[internet publication]
8. National Poison Information Service. TOXBASE. Paracetamol.2023[internet publication]
9. Medical Memoranda,Liver damage and Impaired Glucose Tolerance after Paracetamol Overdosage Brit.med.J;1965; Drug and Therapeutic Bulletin,1966,2,506-507
10. Shah AD,Wood DM,Dargan PI.Understanding lactic acidosis in paracetamol poisoning.BrJ Clin Pharmacol 2010;71:20-8
11. Prescott LF,Roscoe P, Wright N,Brown S.Paracetamol half life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971;1:519-22
12. Rumack BH,Mathew H,Acetamenophen poisoning and toxicity.peddiatrics 1975;55:871-6
13. Daly FF, Fountain JS,Murray L,Graudins A,Buckley NA,Guidelines for the management of paracetamol in Australia and New Zealand- explanation and elaboration.A consessus statement from clinical toxicologists consulting to the Australasian poisons information centres. Med J Aust 2008; 188:296-301

 

Authors and contributors:

Dr. Sher Mohammad, Consultant Anaesthetist(retired), STH NHS Foundation Trust, Sheffield

Dr. Sonia Zafar, Trust Grade Doctor (CT1), General Medicine, York and Scarborough Teaching Hospitals NHS Foundation Trust

Dr. Salman Yahya, Locum Consultant Anaesthesia and ICU, York and Scarborough Teaching Hospitals NHS Foundation Trust

Dr. Danish Imtiaz, Speciality Doctor, Anaesthesia and Intensive Care, University Hospital Leicester

Dr. Parhaizgar Khan, Prof. Anaesthesia, Pak International Medical College, Peshawar

Dr. Gul Rukh, Year-2 Trainee Anaesthesia, Khyber Teaching Hospital, Peshawar.

Dr. Arshad Khan, Locum Registrar Geriatric Medicine, Sherwood Forest Hospitals NHS Foundation Trust

Dr. Ijaz Hussain, Trainee General Medicine, Lady Reading Hospital Peshawar.

Correspondence Address: smyousafzai@doctors.org.uk

 

Image: Canva