Toxicology: Specific Poisons
Paracetamol overdose (OD) is the most common toxicological emergency and the most common cause of liver transplant and death due to poisoning. Patients who start N-acetylcysteine (NAC) within 12 hours of ingestion are very likely to survive.
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Mechanism of action
In overdose, normal pathways
of paracetamol metabolism become saturated, forcing paracetamol down an
alternate pathway: the
first stage is performed by
a cytochrome p450 enzyme, forming a hepatotoxic compound called NAPQI. Under
normal circumstances, the NAPQI is quickly cleared from the liver by
conjugation with glutathione.
After about 10 hours, the
liver’s supply of glutathione is exhausted, and NAPQI accumulates, damaging
cells. Intravenous N-acetylcysteine prevents hepatic damage from NAPQI
by substituting for glutathione; methionine is an oral alternative, given over several days.
Patients at increased risk of toxicity
Drugs that induce p450, such
as anti-epileptics, and chronic alcohol consumption, increase the rate of
formation of NAPQI. Patients with low hepatic glutathione stores, such as those
with HIV, anorexia or cystic fibrosis, may also be at increased risk of
hepatotoxicity.
Management
Measurement of paracetamol
levels before 4 hours after ingestion is unhelpful, except to exclude
paracetamol ingestion. The graph opposite predicts the need for NAC in patients
above the line. NAC is given as a front-loaded infusion. Patients presenting
more than 24 hours after ingestion may still benefit from NAC.
Patients who present more
than 8 hours after ingestion and who have ingested >150 mg/kg paracetamol should have paracetamol levels measured and NAC
commenced on arrival. Other patients should wait until the paracetamol level is
known.
The prothrombin time (PT) is
the single best indicator of hepatic function. Patients whose PT is rising 24
hours after ingestion should continue NAC; a PT level >36 sec at 36 hours suggests serious damage. Hepatic and renal function is
monitored using PT, LFTs and U+Es.
Antidepressants
Tricyclic anti-depressants
(TCAs) such as amitriptyline, imipramine and doxepin are highly toxic in
overdose, and are the second most common cause of overdose deaths. By
comparison, the SSRI antidepressants are much safer in overdose.
The toxic effects of
tricyclic antidepressants are mainly a result of blockade of fast sodium
channels, resulting in membrane-stabilising effects on cardiac and neurological
cells. They also have an anticholinergic action. CNS effects include seizures,
agitation and coma, while cardiotoxicity causes hypotension and ventricular
arrhythmias.
Supportive management with
close monitoring is essential. Acidosis and progressive lengthening of the QTc
may occur. A QRS >120 msec predicts toxicity; >160 msec indicates imminent seizures and/or
ventricular fibrillation (VF).
Sodium bicarbonate is an
effective antidote. The alkali reduces the free drug and the large sodium load
helps overcome the blockade. Phenytoin should not be used for seizures as it
also blocks sodium channels.
Opiates
Opiate overdose causes coma,
hypoventilation and small pupils. Patients who are apnoeic or in whom the cause
for coma is in doubt, e.g. possible trauma, should be given naloxone, a short-
acting antagonist.
In patients who are
breathing, it is best to just give oxygen and wait, as there are hazards in
giving naloxone.
•
Danger to staff from needles around intravenous drug users.
• Naloxone causes acute opiate withdrawal symptoms, which may dissuade drug
users from calling for help in the future.
• Naloxone is short-acting, so there is a danger that a patient may wake,
run away and collapse when the naloxone wears off. Therefore if naloxone is
indicated, it should be a large dose, e.g. 1.6 mg i.m.
In patients who have
(iatrogenic) opiate-induced hypoventilation where one does not want to reverse
the analgesic effect – just
the hypoventilation, this
may be reversed by very small doses of i.v. naloxone
e.g. 40–80 µg. Naloxone infusion may be necessary with long-acting opiates.
Benzodiazepines
Benzodiazepines (BDZ) are
often taken as part of a mixed over- dose. Benzodiazepines have a very good
safety record in overdose and may protect against seizures e.g. when taken with
tricyclic antidepressants.
Flumazenil is a short-acting
benzodiazepine antagonist that can precipitate acute benzodiazepine withdrawal
and intractable seizures, so should not be used in the Emergency Department.
Alcohol
Ethanol is often taken with
overdoses. Paradoxically this may provide a degree of protection from the toxic
effects of some over- doses by competing for metabolic pathways.
Toxic alcohols such as
methanol and ethylene glycol (antifreeze) are metabolised by alcohol
dehydrogenase to toxic compounds. Toxicity can be prevented by either blocking
alcohol dehydogenase using fomepizole, or giving ethanol, which is
preferentially metabolised. The toxic alcohol can be removed by haemodialysis.
Salicylates
Aspirin overdose, while
relatively common, rarely needs treatment. Most patients with significant
overdose complain of tinnitus. Direct stimulation of the respiratory centre
gives initial hyperven- tilation and respiratory alkalosis, progressing later
to a metabolic acidosis. High levels of salicylates indicate the need for
alkaline diuresis (dilute sodium bicarbonate i.v.) or haemodialysis.
Digoxin
Digoxin overdose may be
acute or chronic. Chronic digoxin over- dosage will give bradycardia, and
patients complain of yellow/ green vision – xanthopsia. Acute digoxin overdose
may cause coma, brady- or tachyarrhythmias. Digoxin has a specific antidote – digoxin antibody fragments.
Iron
Iron overdose is uncommon,
but serious. Abdominal X-radiography can identify number and progress of
tablets, and serum iron concentrations predict toxicity. Gastrointestinal
absorption of iron is normally tightly regulated. In overdose, damage to the
gut mucosa allows unregulated iron absorption, exacerbating toxicity. Bowel decontamination
with whole bowel irrigation and chelation using intravenous deferoxamine may be
necessary.
Stuffers and packers
Body stuffers are
usually street-level drug dealers who are caught and decide to swallow the
evidence. Body packers are people who seek to smuggle drugs by
concealing them within the body. Pyrexia >38°C or pulse >120 indicate significant toxicity –
benzodiazepines are useful for agitation.
Stuffers are more likely to
suffer toxic effects as the drugs are not packaged to withstand gastrointestinal
transit, although the drugs are relatively impure, compared to those ingested
by packers. Abdominal radiography and ultrasound can diagnose packers, who need charcoal and whole bowel irrigation.
