Download POISONING BY SPECIFIC PHARMACEUTICAL AGENTS

POISONING BY SPECIFIC
PHARMACEUTICAL AGENTS
• Analgesics Paracetamol Paracetamol
(acetaminophen) is the drug most commonly
used in overdose in the UK. Toxicity results
from formation of an intermediate reactive
metabolite which binds covalently to cellular
proteins, causing cell death. This results in
hepatic and occasionally renal failure. In
therapeutic doses, the toxic intermediate
metabolite is detoxified in reactions requiring
glutathione, but in overdose, glutathione
reserves become exhausted
• Management is summarised in. Activated charcoal
may be used in patients presenting within 1 hour.
Antidotes for paracetamol act by replenishing hepatic
glutathione. Acetylcysteine given intravenously (or
orally in some countries) is highly efficacious if
administered within 8 hours of the overdose.
However, since efficacy declines thereafter,
administration should not be delayed in patients
presenting after 8 hours to await a paracetamol blood
concentration result. The antidote can be stopped if
the paracetamol concentration is shown to be below
the appropriate treatment line. The most important
adverse effect of acetylcysteine is related to doserelated histamine release, the 'anaphylactoid'
reaction, which causes itching and urticaria, and in
severe cases, bronchospasm and hypotension
• Most cases can be managed by temporary discontinuation
of acetylcysteine and administration of an antihistamine.
An alternative antidote in paracetamol poisoning is
methionine 2.5 g orally 4-hourly to a total of four doses,
but it is less effective, especially after delayed
presentation. If a patient presents more than 15 hours
after ingestion, liver function tests, prothrombin time (or
international normalised ratio-INR), renal function tests
and a venous bicarbonate should be measured, the
antidote started, and a poisons information centre or local
liver unit contacted for advice if results are abnormal. An
arterial blood gas sample should be taken in patients with
severe liver function abnormalities; metabolic acidosis
indicates severe poisoning. Liver transplantation should
be considered in individuals who develop life-threatening
liver failure due to paracetamol poisoning
• If multiple ingestions of paracetamol have
taken place over several hours or days (i.e.
a staggered overdose), acetylcysteine
should be given when the paracetamol
dose exceeds 150 mg/kg body weight in
any one 24-hour period or 75 mg/kg body
weight in 'high-risk groups'
• Salicylates (aspirin) Clinical features Salicylate
overdose commonly causes nausea, vomiting,
sweating, tinnitus and deafness. Direct stimulation
of the respiratory centre produces hyperventilation
and respiratory alkalosis. Peripheral vasodilatation
with bounding pulses and profuse sweating occurs
in moderately severe poisoning. Serious salicylate
poisoning is associated with metabolic acidosis,
hypoprothrombinaemia, hyperglycaemia,
hyperpyrexia, renal failure, pulmonary oedema,
shock and cerebral oedema. Agitation, confusion,
coma and fits may occur, especially in children.
Toxicity is enhanced by acidosis, which increases
salicylate transfer across the blood-brain barrie
• Management Activated charcoal should be
administered if the patient presents early. Multiple
doses of activated charcoal may enhance
salicylate elimination but currently are not
routinely recommended. The plasma salicylate
concentration should be measured at least 2 (in
symptomatic patients) or 4 hours (asymptomatic
patients) after overdose and repeated in patients
with suspected serious poisoning, since
concentrations may continue to rise some hours
after overdose. In adults, concentrations above
500 mg/L and 700 mg/L suggest serious and lifethreatening poisoning respectively, although
clinical status is more important than the salicylate
concentration in assessing severity
• Dehydration should be corrected carefully, as
there is a risk of pulmonary oedema, and
metabolic acidosis should be identified and
treated with intravenous sodium bicarbonate
(8.4%), once plasma potassium has been
corrected. Urinary alkalinisation is indicated
for adult patients with salicylate
concentrations above 500 mg/L.
• Haemodialysis is very effective at removing
salicylate and correcting acid-base and fluid
balance abnormalities, and should be considered
when serum concentrations are above 700 mg/L in
adult patients with severe toxic features, or when
there is renal failure, pulmonary oedema, coma,
convulsions or refractory acidosis. Non-steroidal
anti-inflammatory drugs (NSAIDs) Clinical features
Overdose of most NSAIDs (e.g. ibuprofen,
diclofenac, naproxen, indometacin) usually causes
little more than minor abdominal discomfort,
vomiting and/or diarrhoea, but convulsions occur
occasionally, especially with mefenamic acid. Coma,
prolonged seizures, apnoea, liver dysfunction and
renal failure can occur after substantial overdose
but are rare. Features of toxicity are unlikely to
develop more than 6 hours after overdose
• Management Electrolytes, liver function tests
and a full blood count should be checked in
all but the most trivial cases. Activated
charcoal may be given if the patient presents
sufficiently early. Symptomatic treatment for
nausea and gastrointestinal irritation may be
necessary
• Antidepressants Tricyclic antidepressants
(TCAs) TCAs continue to be used
frequently in overdose and carry a high
morbidity and mortality relating to their
sodium channel-blocking, anticholinergic
and α-adrenoceptor-blocking effects
Anticholinergic effects are common. Lifethreatening complications are frequent,
including convulsions, coma, arrhythmias
(ventricular tachycardia, ventricular
fibrillation and, less commonly, heart
block) and hypotension, which results from
inappropriate vasodilatation or impaired
myocardial contractility. Serious
complications appear to occur more
commonly with dosulepin and amitriptyline
• Management Activated charcoal should be administered if
the patient presents sufficiently early. All patients with
possible tricyclic overdose should have a 12-lead ECG and
ongoing cardiac monitoring for at least 6 hours. Prolongation
of the QRS interval (especially if > 0.16 s) indicates severe
sodium channel blockade and is associated with an
increased risk of arrhythmia. Arterial blood gases should be
measured in patients with suspected severe poisoning. In
patients with arrhythmias, severe ECG effects or acidosis,
intravenous sodium bicarbonate (50 mL of 8.4% solution)
should be administered and repeated to correct pH. The
correction of the acidosis and the sodium loading that result
is often associated with rapid improvement in ECG features
and arrhythmias. Hypoxia and electrolyte abnormalities
should also be corrected. Anti-arrhythmic drugs should only
be given on specialist advice. Prolonged convulsions should
be treated with intravenous benzodiazepines
Selective serotonin re-uptake inhibitors (SSRIs)
The SSRIs, including fluoxetine, paroxetine,
fluvoxamine, sertraline and citalopram, are
commonly used to treat depression, in part
because they are less toxic than TCAs. Clinical
features and management Overdose may
produce nausea and vomiting, tremor, insomnia
and sinus tachycardia. Agitation, drowsiness and
convulsions occur infrequently and may be
delayed for several hours after ingestion.
Occasionally, features of serotonin syndrome
may develop, especially if SSRIs are taken in
combination or with other serotonergic agents.
Cardiac arrhythmias, e.g. junctional
bradycardias, occur infrequently. Most patients
require supportive care only.
• Lithium Severe lithium toxicity is uncommon after intentional overdose and
is more often encountered in patients taking therapeutic doses as a result
of drug interactions (e.g. with diuretics or NSAIDs), deteriorating renal
function or dehydration, or because an excessive dose has been
prescribed.
• Clinical features Nausea, diarrhoea, polyuria, dizziness and tremor may
progress to muscular weakness, drowsiness, confusion, myoclonus,
fasciculations, choreoathetosis and renal failure. Coma, convulsions,
ataxia, cardiac dysrhythmias (e.g. heart block), blood pressure
disturbances and renal failure may occur in severe poisoning.
• Management Activated charcoal is ineffective. Gastric lavage is of
theoretical benefit if used early after overdose, but lithium tablets are likely
to remain intact in the stomach and may be too large for aspiration via a
lavage tube. Some advocate whole bowel irrigation after substantial
overdose but efficacy is unknown. Lithium concentrations should be
measured immediately in symptomatic patients or after at least 6 hours in
asymptomatic patients following acute overdose. Adequate hydration
should be maintained with intravenous fluids. Convulsions should be
treated. In patients with features suggesting severe toxicity associated with
high lithium concentrations (e.g. > 4.0 mmol/L after chronic poisoning or >
7.5 mmol/L after acute poisoning), haemodialysis should be considered.
Lithium concentrations are lowered substantially during dialysis but
rebound increases occur after discontinuation, and multiple sessions may
be required
• Cardiovascular medications β-blockers These have negative
inotropic and chronotropic effects. Some have additional
properties that may increase toxicity, such as blockade of
sodium channels (e.g. propranolol) or potassium channels
(e.g. sotalol). Clinical features The major features of toxicity
are bradycardia and hypotension. Heart block, pulmonary
oedema and cardiogenic shock occur in severe poisoning.
Beta-blockers with sodium channel-blocking effects may
cause seizures, confusion and coma, while sotalol may be
associated with repolarisation abnormalities (including QTc
prolongation) and torsades de pointes. Management
Intravenous fluids may reverse hypotension but care is
required to avoid pulmonary oedema. Bradycardia and
hypotension may respond to high doses of atropine (up to 3
mg in an adult). The adrenoceptor agonist isoproterenol
(isoprenaline) may also be effective but high doses are often
needed. Glucagon (5-10 mg over 10 mins, then 1-5 mg/hr by
infusion), which does not act via adrenoceptors, is now more
commonly used
Calcium channel blockers Calcium channel blockers are highly toxic in
overdose via blockade of L-type calcium channels. Dihydropyridines such
as nifedipine or amlodipine affect vascular smooth muscle in particular,
resulting in vasodilatation. 'Rate-limiting' calcium channel blockers such as
diltiazem and verapamil have direct cardiac effects, resulting in
bradycardia and reduced myocardial contractility.
Clinical features Hypotension is associated with vasodilatation and
myocardial depression. Bradycardias and heart block may also occur,
especially with verapamil and diltiazem. Non-cardiac effects include
gastrointestinal disturbances, confusion, metabolic acidosis,
hyperglycaemia and hyperkalaemia. Management Hypotension should be
corrected with intravenous fluids, taking care to avoid pulmonary oedema.
Persistent hypotension may respond to intravenous calcium gluconate (10
mg i.v. over 5 mins, repeated as required). Isoproterenol and glucagon
may also be useful. Successful use of intravenous insulin with glucose
(10-20% dextrose with insulin at 0.5-1.0 U/kg/hr), so-called
'hyperinsulinaemia euglycaemic therapy', has been reported in patients
unresponsive to other strategies. Cardiac pacing may be needed for
severe unresponsive bradycardias or heart block
• Cardiac glycosides (including oleander) Poisoning with digoxin is usually
accidental, arising from prescription of an excessive dose, impairment of
renal function or drug interactions. In South Asia, deliberate selfpoisoning with yellow oleander (Thevetia peruviana), which contains
cardiac glycosides, is common.
• Clinical features Characteristic cardiac effects of toxicity are
tachyarrhythmias (either atrial or ventricular) and bradycardias, with or
without atrioventricular block. Ventricular bigeminy is common and atrial
tachycardia with evidence of atrioventricular block is highly suggestive of
the diagnosis. Severe poisoning is associated with hyperkalaemia. Noncardiac features include confusion, headache, nausea, vomiting,
diarrhoea and (rarely) altered colour vision.
• Management Activated charcoal is commonly administered to patients
presenting early after ingestion of an acute overdose, although evidence
of benefit is lacking. Urea, electrolytes and creatinine should be
measured, a 12-lead ECG performed and cardiac monitoring instituted.
Hypoxia, hypokalaemia (sometimes associated with concurrent diuretic
use), hypomagnesaemia and acidosis increase the risk of arrhythmias
and should be corrected. Significant bradycardias may respond to
atropine, although temporary pacing is sometimes needed. Ventricular
arrhythmias may respond to intravenous magnesium If available,
digoxin-specific antibody fragments should be administered when there
are severe ventricular arrhythmias or unresponsive bradycardias. This
antidote has been shown to be effective for both digitalis and yellow
oleander poisoning.
• Antimalarials Chloroquine Chloroquine is highly toxic; doses of 5 g or
more of chloroquine base are likely to be fatal in an adult. Clinical
features Features of toxicity occur within 1 hour of ingestion and include
nausea, vomiting, agitation, drowsiness, hypokalaemia, acidosis,
headaches and blurred vision. Coma, convulsions and hypotension may
occur in severe poisoning. ECG changes indicating conduction and
repolarisation delay (prolonged QRS and QTc intervals) occur and are
associated with ventricular tachycardia (including torsades de pointes),
ventricular fibrillation and sudden death.
• Management Activated charcoal should be given to all patients
presenting within 1 hour of ingestion of chloroquine in amounts greater
than 15 mg/kg. The cardiac rhythm should be monitored and
dysrhythmias managed. The arterial pH should be corrected, but
hypokalaemia is thought to have a protective effect and should not be
corrected in the first 8 hours after poisoning. High-dose diazepam (2
mg/kg body weight i.v. over 30 mins) has been suggested as having a
protective effect, especially if given in the early stages of severe
chloroquine poisoning, but evidence is limited as yet. Respiratory support
may be required
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Quinine Quinine salts are widely used for treating malaria and leg cramps.
Deaths have been reported with as little as 1.5 g in an adult and 900 mg in a
child.
Clinical features Features of toxicity include nausea, vomiting, tremor, tinnitus
and deafness. Hypotension, haemolysis, renal failure, ataxia, convulsions and
coma are features of serious poisoning. Conduction and repolarisation delay
results in prolonged QRS and QTc intervals on the ECG, and ventricular
tachycardia (including torsades de pointes), ventricular fibrillation and sudden
death may occur. Quinine-induced retinal vasoconstriction and retinal
photoreceptor cell toxicity may result in blurred vision and impaired colour
perception. This usually develops a few hours after overdose and progresses to
constriction of the visual field, scotoma and complete blindness associated with
pupillary dilatation and unresponsiveness to light. Fundoscopy may show retinal
artery spasm, disc pallor and retinal oedema. Although visual loss can be
permanent, some degree of recovery often occurs over several weeks.
Management Multiple-dose activated charcoal should be commenced in patients
who have taken quinine in amounts greater than 15 mg/kg. Gastric lavage may
also be considered if patients have presented within 1 hour. All patients should
have a 12-lead ECG and cardiac monitoring, and their urea, electrolytes and
glucose checked. Dysrhythmias, hypotension, seizures and coma should be
managed as. There are no effective treatments for the visual effects of quinine.
Stellate ganglion block and retrobulbar or intravenous injections of vasodilators
such as nitrates were previously used but are ineffective, as are haemodialysis
and haemoperfusion