time since ingestion is also predictive of toxicity.
Furthermore, concomitant drugs and chronic
alcohol abuse can lower the threshold for toxic
plasma concentrations. The curvilinear nomo-
gram indicating risk of hepatic injury in patients
deemed to be of low or high risk according to
concomitant factors such as alcohol abuse, starts
at 100–190 mg l^1 (about 0.7–1.2 mmol L^1 )at
four hours post-overdose. Plasma concentrations
measured prior to four hours are probably a waste
of time because measures to reduce absorption
should take priority and there is no real estimate
of the size of the exposure.
N-acetylcysteine is a relatively well-tolerated
drug (anaphylactoid reactions can be treated by
halting the infusion for half an hour and administer-
ing an antihistamine). Thus, administration of
N-acetylcysteine can be recommended on an ‘err
on the safe side’ basis, when comparing plasma
concentrations of the toxin with the nomograms on
the package insert of the antidote. Similarly, over-
doses taken in two parts, with some time interval in
between them, should not cause concern when inter-
preting the plasma level: simply assuming that the
whole overdose had been taken on the first occasion
when using the nomograms will againsafely bias the
treatmentdecision.Forthese reasons,the nomogram
for high risk falls to plasma concentrations of zero
when measured 24 h after the overdose; thus, not
only very early after overdose, but also much later,
plasma concentration measurements are pointless.
Oral methionine is probably now an anachronis-
tic treatment even in the absence of peripheral
venous access (intravenous drug abusers). The
importance of treating acetaminophen/paraceta-
mol overdose easily justifies the hazards of a sub-
clavian cannula.
Salicylates
Mention of salicylate overdose is made here, even
though its popularity seems to be in decline. Its
treatment, presuming hemodialysis is not indi-
cated, includes a classic type of beneficial drug
interaction that is different from that of a specific
antidote (cf. N-acetylcysteine, above). Further-
more, the combination of respiratory alkalosis
promoting drug excretion by altering urine pH,
have long attracted Machiavellian examiners set-
ting multiple-choice questions!
Overdoses greater than 150 mg kg^1 (i.e. 20–40
tablets weighing 325 mg each) cause toxicity,
although fatality is related not only to overdose
size but also to the patient’s general condition;
children are sensitive to salicylates disproportio-
nately to their body weight, and are also liable to
more serious metabolic acidosis.
There are usually more acute clinical signs and
symptoms in serious salicylate poisoning (hyper-
ventilation, arterial blood gases, complaints of tin-
nitus, agitation, coma seizures, etc.). Although
plasma salicylate concentrations become interpre-
table at about four hours post-overdose, there is a
greater need to interpret these in the context of the
clinical picture than when acetaminophen/parace-
tamol has been ingested (see Jones and Dargan,
2001). Identifying the peak plasma salicylate con-
centration can be achieved with venous samples
every three hours. CNS toxicity, in particular, indi-
cates serious poisoning, regardless of the plasma
concentration of salicylate.
Hydration to promote diuresis is recommended
in all salicylate overdoses. Urine alkalinization is
generally recommended at plasma concentrations
above 600 mg l^1 salicylate, or half that in children
and the elderly. Even this, however, has its limits,
and hemodialysis at salicylate concentrations of
>800 mg l^1 in adults (half in children and the
elderly), or regardless of plasma concentration
when there are signs of CNS toxicity, is the treat-
ment of choice.
The acid–base aspects to salicylate poisoning
are the following:Salicylate is an organic acid (as the suffix indi-
cates):- It is less ionized in acidic environments.
- It crosses lipid membranes in a concentration-
dependent fashion more easily when not
ionized.
Acidosis must be aggressively treated: - An acid urine inhibits salicylate excretion.
- Acidosis enhances CNS sequestration of
28.2 WHY MONITOR DRUG CONCENTRATIONS? 377