Paracetamol
·
Acetaminophen; N-acetyl-p-aminophenol;
4-hydroxyacetani-lide.
·
Paracetamol exists as white,
odourless, bitter tasting crystals or crystalline powder.
·
Antipyretic: The search for an effective and safe
antipyretic began in the 19th century when Cahn
and Hepp acciden-tally discovered
the fever-reducing property of acetanilide and introduced it into
pharmacotherapeutics as “antifebrin” in 1886.
However its unacceptable toxicity led to a search for less toxic compounds, and
a related compound namely, phenacetin was synthesised and introduced in 1887. This was extensively used till
recently when its role in analgesicnephropathy*
became clear and led to its withdrawal. In1893, von Mering introduced
paracetamol, and a hundredyears later it is still going strong. In fact, paracetamol
is the active metabolite of both acetanilide and phenacetin.
·
Analgesic.
■■ Paracetamol
is rapidly and completely absorbed from the GI tract. Peak plasma levels are
reached in ½ to 1 hour, while the plasma half-life is about 2 hours. Following
an overdose, the peak plasma level is not usually reached for 4 hours.
Absorption may be delayed by other drugs and high carbohydrate foods which
delay gastric emptying.
■■ Protein
binding 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 drug
undergoes hepatic conju-gation with glucuronide and sulfuric acid to form
inactive and harmless metabolites, while 10% is oxidised (through P450
mediation) to N-acetyl-p- benzoquinoneimine (NAPQI) which is a highly reactive
intermediate. NAPQI is capable of covalent binding and arylating critical cell
proteins inducing a series of events that result in cell death. In the normal
course, glutathione rapidly detoxifies this intermediate to cysteine and
mercapturate conjugates. In the overdose situation, glutathione stores become
depleted and the toxic NAPQI binds covalently with hepatocytes of the liver
causing centrilobular hepatic necrosis. However there is significant individual
susceptibility to the toxic effects of paracetamol and upto 20% of seriously
poisoned patients do not develop hepatotoxicity.
■■ Concomitant
intake of drugs which induce P450 enzyme (e.g. phenobarbitone) can enhance the
chances of hepato-toxicity. Alcoholism and chronic therapy with drugs
such as isoniazid and anticonvulsants also predispose to hepatic failure.
·
Stage I (1/2 hr to 24 hrs): Anorexia,
vomiting, sweating,malaise.
·
Stage II (24 to 72 hrs): Relatively
symptom-free. Theremay be right upper quadrant pain. Liver function tests may
be abnormal.
·
Stage III (72 to 96 hrs): Hepatic necrosis
sets in withcoagulation defects, jaundice, and encephalopathy. Nausea and
vomiting reappear. Renal failure and myocardial damage are frequently present.
Death is usually due to hepatic failure and is preceded by coma. Elevated blood
levels of liver enzymes (SGOT/ALT, SGPT/AST) may begin to develop within 24
hours after overdose, and peak 2 to 3 days post-ingestion. Increased total
bilirubin and prolonged PT may also occur in some patients within 24 hours of
paracetamol inges-tion. Decreased serum interleukin-6 (IL-6) has been found to
be associated with hepatic injury following acute paracetamol overdose in a
prospective study. It is suggested that measuring serum IL-6 or C-reactive
protein (a surrogate for IL-6) levels may serve as a prognostic factor in
predicting hepatic injury following an acute overdose.
·
Stage IV (4 days to 2 wks): If the patient
survives theIIIrd stage, complete resolution of hepatic damage is the rule
rather than the exception. There are no reported cases of chronic hepatic
dysfunction from paracetamol.
Additional Manifestations:
––
Hypotension
and shock with hypothermia, in the absence of hepatic dysfunction, have been
reported following acute paracetamol overdose. The mechanism of
paracetamol-induced hypoten-sion is unclear.
–– Myocardial injury (with ECG
changes and CPK MB elevations) has occasionally been reported in severe
overdose. It is unclear if paracetamol is a direct myocardial toxin, or if
these effects are secondary to metabolic or cardiopulmonary abnormalities
induced by severe paracetamol toxicity.
–– Coma and metabolic acidosis
within 3 to 4 hours of ingestion have been described rarely.
–– Acute pancreatitis with
hyperamylasaemia has been reported following paracetamol overdose.
–– Acute alcohol ingestion in
chronic alcohol abusers had a protective effect against hepatic
encepha-lopathy. In patients who were not alcohol abusers and either took an
acute alcohol ingestion or did not take any alcohol, only a non-significant
trend toward a protective effect of acute alcohol inges-tion was shown.
Therapeutic doses of paracetamol do not appear to cause hepatotoxicity in
chronic alcoholics.
––
Adolescents are 6 times more likely to develop liver damage and 2 times
more likely to develop poten-tially toxic levels than children less than 6
years 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 blood
lactate levels may be seen early (12 hours), especially in severe overdoses.
Metabolic acidosis is common 3 to 4 days after ingestion in patients developing
hepatic failure.
–– Hyperphosphataemia (>1.2
mmol/L) appears to be an early predictor of nonsurvival in severe
paracetamol-induced hepatotoxicity (ALT >1000 U/L; hepatic encephalopathy;
liver transplanta-tion) at 48 to 96 hours post-ingestion. The degree of
hyperphosphataemia in fatalities has correlated with renal function. It is
proposed that hyperphos-phataemia is due to renal dysfunction in the absence of
hepatic regeneration (which is associated with lowering of serum phosphate).
Hypophosphataemia has been reported, may occur in the absence of hepatic
encephalopathy, and may be suggestive of a subclinical renal effect.
o This is uncommon, but cases have
been reported where-in an individual has consumed large doses of paracetamol
over a period of time for relief of chronic pain which resulted in toxic
hepatitis. This is more common in alcoholics, AIDS patients (in whom there is
depletion of glutathione), and patients receiving other medications which are
cytochrome P450 inducers, e.g. isoniazid, rifampicin, phenytoin, carbamazepine,
and barbiturates.
o Chronic overdose among children is
more 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 that
either paracetamol or N-acetylcysteine is teratogenic. Paracetamol overdose
does not appear to increase the risk for birth defects or adverse pregnancy
outcome unless severe maternal toxicity results.
o There is no evidence that
paracetamol is carcinogenic.
o In fact, in a case control study,
patients who ingested paracetamol were at decreased risk of developing ovarian
cancer.
·
About 20 to 25 grams. However doses
as 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 years
appear to be more resistant to the toxic effects of paracetamol. It has been
suggested that the toxic dose for a 5-year-old child, based on liver size ratio
compared to an adult, is 187.5 mg/kg. Predicted toxic dose for a younger child
would be even higher.
·
In a prospective, observational
study of acute paediatric overdose ingestions of paracetamol (excluding
extended- release preparations) of up to 200 mg/kg, some investigators found
that with home monitoring alone these patients do not develop signs or symptoms
of hepatic injury at 72-hour follow-up.
·
Liver may be enlarged and yellowish
in colour. Microscopy reveals centrilobular necrosis.
·
Histological evidence of renal
damage.
·
Cerebral oedema.
·
Cardiac findings in fatal overdoses
have included suben-docardial haemorrhages, fatty degeneration, and focal
necrosis.
■■ Attempted
suicide with paracetamol accounts for a stag-gering 15 to 30% of cases of
poisoning in the UK; a similar scenario exists in the USA where paracetamol
overdose accounts for more hospitalisations than any other pharma-ceutical
agent. While the situation is at present not as bad in India, there are
alarming indications of rising incidence.
■■ Accidental
poisoning most often results from inadvertent therapeutic overdose either as an
acute or as a chronic phenomenon. A few cases result from hypersensitivity
reactions which (though rare) may sometimes produce serious manifestations
ranging from dermal to respiratory to anaphylactoid reactions.
■■ As
of November 1997, the FDA (USA) requires an alcohol warning on all over-
the-counter pain relievers, which includes paracetamol, aspirin, other
salicylates, ibuprofen, ketoprofen, and naproxen sodium due to a potential drug
interaction resulting in upper GI bleeding or liver damage.
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