Kirsch, R. E.

Pillans, P.

Robson, S. C.

Spearman, C. W.

University of Queensland eSpace

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CLINICAL PRACTICE
Paracetamol poisoning
Paracetamol is one of the most widely used anal-gesic/antipyretic agents because of its overall effi-cacy and safety. However, paracetamol overdose is
the most imponant cause of acute liver failure in the
UK and is not uncommon in South Africa. 1
Liver damage usually occurs with ingestion of
approximately 7,5 g paracetamol, and doses of 12 - 16 g
commonly result in fatal acme liver failure. Prior long-
term use of enzyme-inducing agents such as alcohol,
anticonvulsant drugs (phenytoin) and antiruberculosis
therapy may enhance paracetamol toxicity so that doses
of 6 - 8 g may be fata!.' If alcohol and paracetamol are
taken together in an overdose, then alcohol may decrease
metabolism of paracetamol to reactive metabolites either
by direct competition for cytochrome P-450 or as a
result of indirect inhibition of cytochrome P-450 by
depletion of cytosolic-reduced NADPH.
Clinical picture
The initial onset of gastro-intestinal liver damage is
rapid, with anorexia, nausea and vomiting occurring
within a few hours of ingestion of a hepatotoxic dose.
These are followed by abdominal pain and liver tender-
ness which may persist for 36 - 72 hours.
Liver failure may then worsen, particularly if the ini-
tial prothrombin international normalised ratio (INR)
values are in excess of 2,2 and if bilirubin levels increase
to more than 68 /lmoI/l.
Overall monality rates are about 2 - 13%; fulminant
liver failure tends to occur between days 3 and 6. If
patients recover, results of liver tests usually return to
normal within 7 - 20 days and there is no residual
hepatic damage. Renal failure secondary to acute tubu-
lar necrosis is common and patients may require dia-
lysis.'
Metabolism ofparacetamol
Paracetamol is modified via several routes, some of
which are detoxifying, while others lead to the produc-
tion of toxic metabolites. Usually about 70 - 80% of the
parent drug is conjugated to form non-toxic sulphates
and glucuronides which are then excreted in the urine;
5 - 10% of paracetamol is excreted as glutathione-
derived conjugates (3-cysteinyl, 3-mercaprurate and
3-methyl conjugates). These thio-ethers are the detoxifi-
cation products of the reactive and toxic metabolite
of paracetamol, N-acetyl-p-benzo-quinone-imine
(NAPQI).
Approximately 5 - 10% of the dose is excreted as 3-
hydroxy- and 3-methoxyacetaminophen metabolites.
Like the thio-ethers, their formation clearances decrease
with increasing doses and they are found in large
amounts in urine taken from overdosed patients."
Mechanisms ofNAPQI toxicity
NAPQI thus appears to be the major toxic metabolite.
In overdose, larger amounts of paracetamol are
metabolised by oxidation as a result of saturation of the
sulphate/glucuronide conjugate pathway. Hepatotoxicity
occurs when hepatic glutathione stores become depleted
and the liver is no longer able to detoxify NAPQI.
Hepatocellular injury may occur as a result of covalent
binding of NAPQI to hepatocyte proteins, particularly
mitochondrial proteins, resulting in cell injury. NAPQI
is a powerful oxidant, panicularly of cellular thiols and
pyridine nucleotides, and this results in extreme oxida-
tive stress and lipid peroxidation with the generation of
superoxide anions. Finally, NAPQI depletes cellular
protein and non-protein thiols; arylation (covalent bind-
ing) of thiols appears to be more damaging than s-thio-
lation. Depletion of cellular thiols results in inhibition of
calcium ATPase and loss of the ability of mitochondrial
proteins to sequestrate Ca". This results in sequential
increases in cytosolic Ca" concentrations, mitochondrial
Ca" cycling, activation of proteases and endonucleases
with consequent hepatocellular injury."
Use ofN-acetylcysteine
N-acetylcysteine is the antidote of choice in the treat-
ment of paracetamol overdose. It protects against hepa-
totoxicity by replenishing intracellular glutathione stores
and decreasing covalent binding of paracetamol to hep-
atic proteins.' Late administration of N-acetylcysteine
potentially still offers some protection against hepato-
toxicity, as glutathione generated from cysteine releases
covalently bound NAPQI from arylated proteins and
restores s-thiolated proteins to their reduced state.
There are funher mechanisms influencing microvascular
integrity which may facilitate recovery of end-organ
function." In view of the potentially fatal outcome of
paracetamol intoxication, we have proposed the follow-
ing management scheme which should be both clinically
effective and safe. It is hoped that the application of this
protocol will prevent avoidable deaths from this mode of
poisoning.
Protocol for the management ofacute
paracetamol poisoning
1. Suspected significant paracetaInol overdose
presenting less than 24 hours after ingestion.
(a) If a significant ingestion of paracetamol is sus-
pected or if the patient is unconscious and neither the
dose nor the time of ingestion are known, or if a delay in
obtaining paracetamol blood levels is anticipated, then
intravenous N-acetylcysteine therapy must be com-
menced immediately. Paracetamol levels must be esti-
mated as an emergency investigation whenever possible,
and the result plotted on the accompanying graph
(Fig. 1). If the paracetamol level is well below the treat-
ment line, liver damage is unlikely, and N-acetylcysteine
should be stopped. If the paracetamol level is just below
or above the treatment line, the intravenous infusion of
N-acetylcysteine must be continued as liver damage is
highly likely.
(b) A patient with a high level of paracetamol in the
blood less than 4 hours after ingestion must receive N-
acetylcysteine. However, sub-toxic levels less than 4
hours after ingestion of the overdose may be misleading
because absorption is incomplete. Levels should there-
fore be checked again at 4 hours.
(c) Patients who have taken an overdose within 2
hours (8 - 12 hours if in coma or when there has been
.concomitant ingestion of other drugs which delay gastric
emptying) of presentation to hospital must undergo
gastric lavage and should receive activated charcoal, par-
ticularly if there is suspicion of ingestion of other drugs
which may delay gastro-intestinal transit time and may
be toxic in their own right (viz. opioids and tricyclics).
2. Delayed presentation after paracetaInol
overdose. Patients presenting after more than 24 hours
should have liver enzymes, prothrombin, INR and
blood paracetamol levels tested. If any paracetamol is
detected, or if liver function test results are abnormal, or
if ingestion of a toxic dose is suspected, the patient
should be admitted to hospital for observation and
management.
----------------------------------.,
CLINICAL PRACTICE
220
1,4
200
180 ------------ 1,2
E 160
......
---------- 1,0Cl
:i. 140
0 Treatment LineE
ctl 120 --------- 0,8QJ
t)
~ 100ctl
0.. 0,6
ctl
E 80
en
ctl
ii 60 ---- 0,4
40
0,2
20
0 0
4 6 8 10 12 14
Hours after ingestion
FIG. 1.
Graph on which estimated paracetamol levels should be
plotted.
This patient may be reviewed by pharmacologists
and physicians experienced in the management of liver
failure and drug intoxication, and must receive early
supportive therapy in hospital.
The use of N-acerylcysteine in these circumstances is
controversial, bur it should probably be given if para-
cetamol is still detectable in the blood.
3. Probable non-significant paracetamol over-
dose. If it is reasonably cenain that less than 7,5 g have
been taken, liver damage is unlikely. Activated charcoal
should be administered to bind the drug in the gasrro-
intestinal tracr. If, however, blood levels show poten-
tially toxic paracetamol levels, intravenous N-acetyl-
cysteine must be administered.
4. Specific antidote. The dose of N-acerylcysteine
(Parvolex), which is available in 10 ml ampoules con-
taining 2 g (200 mg/m!), is administered as an infusion
as follows: 150 mglkg in 200 rnl 5% dextrose water over
15 minutes. Then 50 mg/kg in 500 ml 5% dextrose
water over 4 hours, then 100 mg/kg in 1 litre of 5% dex-
trose water over 16 hours. A total of300 mglkg Parvolex
is therefore administered over approximately 20 hours.
The serious side-effects from this infusion are uncom-
mon but include allergic manifestations, anaphylactic
reactions, ECG changes and electrolyte disturbances.
Careful monitoring is indicated, particularly in patients
with asthma. It should also be stressed that ECG and
electrolyte changes may in any event be' seen in para-
cetamol overdose.
Oral methionine, another precursor for hepatic
glutathione, is inferior to N-acetylcysteine because of the
risks of vomiting and impaired conversion to glutathione
in the setting ofliver dysfunction.
5. Supportive therapy. This is important and
includes adequate fluid, electrolyte and vitamin replace-
ment. Antihistamine anti-emetics are recommended
if required. Conventional anti-liver failure treatment
should be initiated if the coagulation disturbances are
pronounced (INR 2,5 on the second or third day after
overdose), or if liver enzyme levels are extraordinarily
high (AST greater than 5 000 U/l). At this point a spe-
cialist centre with intensive care facilities should be con-
tacted.
Conclusions
These recommendations are guidelines only, as clinical
judgement is most important. If in doubt, it is better to
err on the side of caution and to administer N-acetylcys-
teine intravenously while awaiting drug levels. A signifi-
cant paracetamol overdose is a true medical emergency
as the development of acute established liver failure has
a high mortality rate.
C. W. SPEARMAN
S.C.ROBSON
R..E. KlRSCH
P.PILLANS
MRClUCT Liver Research Centre, Emergency Unit
Departments of Medicine and Phannacology
Universiry of Cape Town
1. Hift R], Robson SC, Kirsch RE. Drug-induced liver disease.
CMEIVMO 1992; 10: 1567-1578.
2. Bray GP, Harrison PM, O'Grady ]G, Tredger ]M, Williams R.
Long-term anticonvulsant therapy worsens ourcome in paracera-
mol-induced fulminant hepatic failure. Hum Exp Toxicol 1992; 11:
265-270.
3. Davidson DGD, Eastham WN. Acute liver necrosis following over-
dose of paracetamol. BMJ 1966; 2: 497-499.
4. Nelson SO. Molecular mechanisms of the heparotoxiciry caused by
acetaminophen. Semi" Liver Dis 1990; 10: 267-278.
5. Keays R, Harrison PM, Wendon ]A, et al. Intravenous acerylcys-
teine in paracetamol-induced fulminant hepatic failure: a prospec-
tive controlled trial. BMJ 1991; 303: 1026-1029.
6. Harrison PM, Keays R, Bray GP; Alexander G]M, Williams R.
Improved outcome of paracetamOl-induced fulminant hepatic fail-
ure by late administration of acerylcysteine. Lancer 1990; 335:
1572-1573.
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Paracetamol Poisoning

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