Biology of Disease

COMMON POISONS

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY ('(

Figure 12.7 An overview of the detoxification

and toxic effects of paracetamol. See text for

details.

Paracetamol

UDP glucuronyl

transferase

Arylsulpho

transferase

Cytochrome

P-450

Glucuronide

conjugate

(nontoxic)

Sulfate

conjugate

(nontoxic)

N-acetylbenzoquinoneimine

Glutathione

Glutathione

conjugate

Paracetamol

3-mercapturic acid

(nontoxic)

Binding to cell

constituents, causing

hepatotoxicityand

nephrotoxicity

Toxic doses

A dose of 15 g for adults and 4 g for children is normally sufficient to cause
hepatotoxicity. It has been suggested that this amount of paracetamol
depletes liver glutathione concentrations by 70% in a 70 kg man. However,
there is wide variation in the metabolic handling of paracetamol by the
body and large overdoses of over 50 g have been known to have little effect
in some patients. The incidence of hepatotoxicity in children is significantly
lower at concentrations of paracetamol in blood that would be potentially
toxic in adults. Animal studies have suggested that turnover of glutathione
is age dependent, hence younger animals can tolerate higher doses of
paracetamol.

Often estimates of the amount of paracetamol ingested, for example by a
potential suicide, are unreliable. Thus, predictions of hepatotoxicity should be
made only on the basis of serum concentrations. In general, concentrations
of paracetamol greater than 300 mg dm–3 cause serious liver damage 4 h after
ingestion whereas values below 120 mg dm–3 show no toxicity.

Clinical features of paracetamol poisoning

The signs and symptoms of paracetamol overdose are insidious, especially in
the earlier stages. The clinical features can be divided into three phases, with
a fourth occurring if the person survives toxicity and are described in Table
12.2.