Paracetamol - Analgesic-Antipyretics (2025)

Synonyms: Acetaminophen; N-acetyl-p-aminophenol; 4-hydroxyacetani-lide.Physical Appearance: Paracetamol exists as white, odourless, bitter tasting crystals or crystalline powder.

Paracetamol

Synonyms

·Acetaminophen; N-acetyl-p-aminophenol;4-hydroxyacetani-lide.

Physical Appearance

·Paracetamol exists as white,odourless, bitter tasting crystals or crystalline powder.

Uses

·Antipyretic: The search for an effective and safeantipyretic began in the 19th century when Cahnand Hepp acciden-tally discoveredthe fever-reducing property of acetanilide and introduced it intopharmacotherapeutics as “antifebrin” in 1886.However its unacceptable toxicity led to a search for less toxic compounds, anda related compound namely, phenacetin was synthesised and introduced in 1887. This was extensively used tillrecently when its role in analgesicnephropathy*became clear and led to its withdrawal. In1893, von Mering introducedparacetamol, and a hundredyears later it is still going strong. In fact, paracetamolis the active metabolite of both acetanilide and phenacetin.

·Analgesic.

Toxicokinetics and Mode of Action

■■ Paracetamolis rapidly and completely absorbed from the GI tract. Peak plasma levels arereached in ½ to 1 hour, while the plasma half-life is about 2 hours. Followingan overdose, the peak plasma level is not usually reached for 4 hours.Absorption may be delayed by other drugs and high carbohydrate foods whichdelay gastric emptying.

■■ Proteinbinding for paracetamol is 5 to 20%. Volume of distribution is 0.8 to 1 L/kg(adult). The half-life of paracetamol may exceed 12 hours in acute overdose.

■■Normally about 90% of the drugundergoes hepatic conju-gation with glucuronide and sulfuric acid to forminactive and harmless metabolites, while 10% is oxidised (through P450mediation) to N-acetyl-p- benzoquinoneimine (NAPQI) which is a highly reactiveintermediate. NAPQI is capable of covalent binding and arylating critical cellproteins inducing a series of events that result in cell death. In the normalcourse, glutathione rapidly detoxifies this intermediate to cysteine andmercapturate conjugates. In the overdose situation, glutathione stores becomedepleted and the toxic NAPQI binds covalently with hepatocytes of the livercausing centrilobular hepatic necrosis. However there is significant individualsusceptibility to the toxic effects of paracetamol and upto 20% of seriouslypoisoned patients do not develop hepatotoxicity.

■■ Concomitantintake of drugs which induce P450 enzyme (e.g. phenobarbitone) can enhance thechances of hepato-toxicity. Alcoholism and chronic therapy with drugssuch as isoniazid and anticonvulsants also predispose to hepatic failure.

Clinical (Toxic) Features

Acute Poisoning:

·Stage I (1/2 hr to 24 hrs): Anorexia,vomiting, sweating,malaise.

·Stage II (24 to 72 hrs): Relativelysymptom-free. Theremay be right upper quadrant pain. Liver function tests maybe abnormal.

·Stage III (72 to 96 hrs): Hepatic necrosissets in withcoagulation defects, jaundice, and encephalopathy. Nausea andvomiting reappear. Renal failure and myocardial damage are frequently present.Death is usually due to hepatic failure and is preceded by coma. Elevated bloodlevels of liver enzymes (SGOT/ALT, SGPT/AST) may begin to develop within 24hours after overdose, and peak 2 to 3 days post-ingestion. Increased totalbilirubin and prolonged PT may also occur in some patients within 24 hours ofparacetamol inges-tion. Decreased serum interleukin-6 (IL-6) has been found tobe associated with hepatic injury following acute paracetamol overdose in aprospective study. It is suggested that measuring serum IL-6 or C-reactiveprotein (a surrogate for IL-6) levels may serve as a prognostic factor inpredicting hepatic injury following an acute overdose.

·Stage IV (4 days to 2 wks): If the patientsurvives theIIIrd stage, complete resolution of hepatic damage is the rulerather than the exception. There are no reported cases of chronic hepaticdysfunction from paracetamol.

Additional Manifestations:

––Hypotensionand shock with hypothermia, in the absence of hepatic dysfunction, have beenreported following acute paracetamol overdose. The mechanism ofparacetamol-induced hypoten-sion is unclear.

–– Myocardial injury (with ECGchanges and CPK MB elevations) has occasionally been reported in severeoverdose. It is unclear if paracetamol is a direct myocardial toxin, or ifthese effects are secondary to metabolic or cardiopulmonary abnormalitiesinduced by severe paracetamol toxicity.

–– Coma and metabolic acidosiswithin 3 to 4 hours of ingestion have been described rarely.

–– Acute pancreatitis withhyperamylasaemia has been reported following paracetamol overdose.

–– Acute alcohol ingestion inchronic alcohol abusers had a protective effect against hepaticencepha-lopathy. In patients who were not alcohol abusers and either took anacute alcohol ingestion or did not take any alcohol, only a non-significanttrend toward a protective effect of acute alcohol inges-tion was shown.Therapeutic doses of paracetamol do not appear to cause hepatotoxicity inchronic alcoholics.

––Adolescents are 6 times more likely to develop liver damage and 2 timesmore likely to develop poten-tially toxic levels than children less than 6years old.

–– Transient renal damage may occur.Nephrotoxic effects include acute tubular necrosis, flank pain, haematuria,proteinuria, and an antidiuretic hormone effect.

–– Metabolic acidosis and high bloodlactate levels may be seen early (12 hours), especially in severe overdoses.Metabolic acidosis is common 3 to 4 days after ingestion in patients developinghepatic failure.

–– Hyperphosphataemia (>1.2mmol/L) appears to be an early predictor of nonsurvival in severeparacetamol-induced hepatotoxicity (ALT >1000 U/L; hepatic encephalopathy;liver transplanta-tion) at 48 to 96 hours post-ingestion. The degree ofhyperphosphataemia in fatalities has correlated with renal function. It isproposed that hyperphos-phataemia is due to renal dysfunction in the absence ofhepatic regeneration (which is associated with lowering of serum phosphate).Hypophosphataemia has been reported, may occur in the absence of hepaticencephalopathy, and may be suggestive of a subclinical renal effect.

Chronic Poisoning:

o This is uncommon, but cases havebeen reported where-in an individual has consumed large doses of paracetamolover a period of time for relief of chronic pain which resulted in toxichepatitis. This is more common in alcoholics, AIDS patients (in whom there isdepletion of glutathione), and patients receiving other medications which arecytochrome P450 inducers, e.g. isoniazid, rifampicin, phenytoin, carbamazepine,and barbiturates.

o Chronic overdose among children ismore common than in adults mainly because of dose miscalculation by parents.Features include anorexia, vomiting, lethargy, low body temperature,hepatomegaly, and oliguria.

o There is no clear evidence thateither paracetamol or N-acetylcysteine is teratogenic. Paracetamol overdosedoes not appear to increase the risk for birth defects or adverse pregnancyoutcome unless severe maternal toxicity results.

o There is no evidence thatparacetamol is carcinogenic.

o In fact, in a case control study,patients who ingested paracetamol were at decreased risk of developing ovariancancer.

Usual Fatal Dose

·About 20 to 25 grams. However dosesas low as 10 grams can cause serious hepatotoxicity. Ingestion of even 150 mg/kg or 7.5 grams has caused liver injury.

·Children under the age of 10 yearsappear to be more resistant to the toxic effects of paracetamol. It has beensuggested that the toxic dose for a 5-year-old child, based on liver size ratiocompared to an adult, is 187.5 mg/kg. Predicted toxic dose for a younger childwould be even higher.

·In a prospective, observationalstudy of acute paediatric overdose ingestions of paracetamol (excludingextended- release preparations) of up to 200 mg/kg, some investigators foundthat with home monitoring alone these patients do not develop signs or symptomsof hepatic injury at 72-hour follow-up.

Autopsy Features

·Liver may be enlarged and yellowishin colour. Microscopy reveals centrilobular necrosis.

·Histological evidence of renaldamage.

·Cerebral oedema.

·Cardiac findings in fatal overdoseshave included suben-docardial haemorrhages, fatty degeneration, and focalnecrosis.

Forensic Issues

■■ Attemptedsuicide with paracetamol accounts for a stag-gering 15 to 30% of cases ofpoisoning in the UK; a similar scenario exists in the USA where paracetamoloverdose accounts for more hospitalisations than any other pharma-ceuticalagent. While the situation is at present not as bad in India, there arealarming indications of rising incidence.

■■ Accidentalpoisoning most often results from inadvertent therapeutic overdose either as anacute or as a chronic phenomenon. A few cases result from hypersensitivityreactions which (though rare) may sometimes produce serious manifestationsranging from dermal to respiratory to anaphylactoid reactions.

■■ Asof November 1997, the FDA (USA) requires an alcohol warning on all over-the-counter pain relievers, which includes paracetamol, aspirin, othersalicylates, ibuprofen, ketoprofen, and naproxen sodium due to a potential druginteraction resulting in upper GI bleeding or liver damage.

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Modern Medical Toxicology: Miscellaneous Drugs and Poisons: Analgesics and Antihistamines : Paracetamol - Analgesic-Antipyretics |