Paracetamol and Aspirin
Poisoning
Dr. SH Tsui
23 March 2005
Paracetamol
• Very Common
– 1054 registered pharmaceuticals
contain paracetamol in HK
• Perceived to be benign
– But it can be lethal
• Treatable
– Early antidote
Poisoning Data
• Local – UCH database
– About 1000 cases
– Paracetamol 16%
• US - TESS 2002
– 2.3 million exposure
– Analgesics 10.8%
– Paracetamol 4.9%
– Salicylates 0.8%
QMH data
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May to October 1998
Total cases of DO: 205
Paracetamol involved: 33 (16%)
Mortality: nil
Paracetamol found without a history of
intake: 4
• With potentially toxic level: 1 out of 4
Who will manage this case in
A&E/Observation ward?
• Young lady taken 12 tabs of panadol 3 hours
ago?
• Young man taken 20 tabs of panadol half an
hour ago?
• Paracetamol level at 4hr came back to be
896mol/L, LFT normal
Who will continue to manage?
Who will start NAC?
• Who will give full course of NAC in their O ward?
Pharmacokinetics
• Potential toxic dose
– >150mg/kg
• Rapid absorption
– Peak within 1-2 hour
• Vd – 1L/kg
• T1/2
– 2-3 hours,
– Increased in overdose
Metabolism
• Non toxic metabolites
APAP
– Sulfate conjugate
– Glucuronide conjugate
• Toxic metabolites
– NAPQI
Urine
(unchanged)
• Determinants
– Dose
– P450 activity
– 2E1 – polymorphism
results in different
susceptibility
– Glutathione
>90%
Sulfate
Glucuronide
cytochrome
P450 (IIE1, IA2, IIIA4)
NAPQI
Glutathione
Glutathione depleted
Mercapturic acid
conjugates
Cell Damage
Liver toxicity
• Central zone
– Highest
concentration of
P450
– Lowest oxygen
content
• Massive centrilobular necrosis
Risk factors for liver toxicity
• Enzyme induction: smoking, barbituates,
phentoin, isoniazids, ethanol
• Decreased glutathione store: malnutritionalcoholism, HIV, chronic illness
Renal toxicity
– Consistent with acute
tubular necrosis
– P 450 in kidney
– NAPQI formation
– Not hepato-renal
initially
In massive overdose
• CNS
– Coma
– P450 in brain, ? Mechanism
• Metabolic
– Metabolic acidosis, mitochondria dysfunction
• Coagulopathy
– Directly interfere with coagulation factors
– Later 2o to liver failure
Clinical Presentation
I
0.5-24
Hours
Nausea, vomiting, anorexia, pallor, or entirely
normal appearance
II
18-72
Hours
Progressive laboratory and clinical signs of hepatic
injury
III
72-96
Hours
Hepatic failure
Multi-organ failure
IV
4 to 14
Days
Recovery or death
Liver is entirely normal after recovery
Must Screen Level
• Paracetamol level
– Approximately 1/500 poisoned cases
where there is no history of paracetamol
overdose has a level requiring therapy
– Cost effective
Ashbourne: Ann Emerg Med 1989:18:1035
Kulig: Ann Emerg Med 1985;14:562
Sporer KA, Am J Emerg Med.1996;14:443-6
Treatment
• GI decontamination
• Antidote
• Liver failure
– Supportive
– Transplant
GI decontamination
• Early (< 4 hours)
– Activated charcoal
– GL for co-ingestion only
• Late
– No indication for decontamination in
pure overdose
– Activated charcoal consideration in
mixed overdose
Natural History of Untreated Overdose
Mortality
< 5%
Hepatic failure
5-10%
Clinical hepatitis
20-40%
Chemical hepatitis
50-70%
Renal failure
10%
Efficacy of NAC
– <8 hours - no morbidity and mortality
– 8- 24 hours, 10-30% had AST>1000
Smilkstein: N Engl J Med 1988;319:1557
– 10-36 hours, reduce mortality in
fulminant hepatic failure
(58% Vs 37%)
Harrison: Lancet. 1990 Jun 30;335(8705):1572-3
– 36-80 hours, reduce mortality
(48% Vs 20%)
Keays: Brit Med J 1991;303:1026
Smilkstein: N Engl J Med
1988;319:1557
Antidote : N-acetylcystecine
• Mechanism of action in early phase
– Major
• Increases non-toxic sulfation
• Precursor for glutathione
– Minor
• Directly conjugates NAPQI
• Directly reduces NAPQI back to
Paracetamol
Antidote : N-acetylcystecine
• Mechanism of action in late phase
– Non-specific antioxidant
– Impairs WBC migration to injury
– Improves hepatic oxygen extraction
Harrison: N Engl J Med 1991;324:1852
– Improves cardiac output
Harrison: N Engl J Med 1991;324:1852
Indications for NAC Therapy
–
Level available < 8 hours
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•
–
Level not available < 8 hours post ingestion
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•
–
Treat first
Make decision to continue or stop therapy based on level
Late Presentation (>24 hrs post-ingestion)
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•
–
Wait for level
Treat if above nomogram
Detectable paracetamol level
Elevated AST
Fulminant liver failure
Nomogram
• Paracetamol (g/ml) = 0.15 x Paracetamol (mol/L)
Drawbacks of Normogram
• Refers to single acute ingestion
• Applicability to young children never been
proved
• Time of ingestion not always accurate in
real life situation
• Does not predict life or death
IV NAC dose
• 150mg/kg in 200ml D5 over 1 hour
then
• 50mg/kg in 500ml D5 over 4 hours
then
• 100mg/kg in 1000ml D5 over 16
hours
• Total dose 300mg/kg in 21 hours
• Rate-related side effect
Anaphylactoid reaction
Rash, utricaria, bronchospasm, hypotension
Treatment of liver failure
• Supportive treatment
– NAC
• 150mg/kg every 24 hours till death or recovery
– Plasmapheresis
– Bioartificial Liver (BAL)
• Liver transplants
– 50% survival in 10 years
– Clinical Predictors
Predictors of death in Paracetamol
liver failure
• Kings College’s criteria
• Newer Predictors
– Lactate
• pH < 7.30 after volume
– Phosphate
resuscitation OR
• Combination of 3 parameters
– Stage III or IV encephthalopathy
– PT > 100 seconds
– Creatinine above 300µmol/L
O’Grady: Gastroenterology 1989:97:439
Extended Release Preparations
• First marketed in
1994
• Bilayered preparation
contains ~650mg of
paracetamol
• Delayed dissolution
and release of half of
the drug
Observations from case reports
• 13 patients with overdose of ER
formulation
• Elimination phase was delayed in 8
patients
• 3 patients had non-toxic levels at 4hr
subsequently had levels in toxic range
Cetaruk: Ann Emerg Med 1997; 30: 104-8
Recommendations
• Check levels at 4 hour and then 4-6hrs
later
• NAC if either value is above treatment line
• If 2nd level> 1st level, or lies close to toxic
range, start NAC and obtain additional
measurements
Temple: N Eng J Med. 1995; 333: 1058-9
How about Fast Acting
Paracetamol?
• Paracetamol &
sodium bicarbonate
• Doubles the
absorption rates
• Syrup panadol
overdose (Also fast
absorption)
Repeated Supra-therapeutic
intake
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•
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•
•
>4gm for 24hr or more
>90mg/kg/day for 24hr or more
GI decontamination not a priority
Normogram not applicable
NAC if detectable paracetamol level or
elevated liver enzyme
• Continue NAC until 24hrs after last dose
or improvement of patient
Summary – Paracetamol
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Common overdose
No clear early toxidrome
Must screen with level
Early therapy very effective
Late therapy still efficacious
Identify high risk patients for
transfer to liver transplant unit
Salicylates
• Common anti-inflammatory, analgesic,
antipyretics, and anti-platelet agent
– 57 and 132 registered pharmaceuticals in
HK contain aspirin and salicylate
• Different preparations
– Aspirin (acetyl salicylic acid) tablets
– Enteric coated
– Topical Preparations (methyl salicylate)
• Dangerous -7gm of salicylate in 5 ml
Pharmacokinetics
• Absorption
– Tablets dissolution is the rate
determining step
– Formation of concretion
– Pyloric spasm
– Significant dermal absorption,
especially in diseased skin
Brubacher JR: J tox clin tox 1996; 34(4):431-6
• Distribution
– High protein-bound
• saturated in overdose
– Vd -0.15 → 0.35 L/kg
– pH effect
• Weak acid. pKa 3
pH effect
• Alkalemia
•
pH of serum higher than that of CSF
• HA Can cross membrane
pH ↓
pH ↑
• Acidemia
•
H+
A- Cannot cross membrane
•
pH in serum lower than that of CSF
Metabolism & Excretion
• Therapeutic
– Hepatic conjugation with glucuronic acid or
glycine
– Renal elimination insignificant
• Overdose
– Hepatic conjugation saturated
– Renal elimination become important
Pathophysiology
• Uncouple the oxidative
phosphorylation
– Short circuit the
mitochondria membrane
potential
– Generate heat instead
• Inhibits dehydrogenase in
Kreb’s cycle
HA
X
H+A-
Clinical Manifestation
CNS
– Tinnitus or hearing
impairment
– Confusion, lethargy,
coma, seizure
– Cerebral edema
– Death
Clinical Manifestation
• Acid/Base
– Early respiratory alkalosis
• Hyperventilation by ↑RR
or/and ↑TV
– Mixed metabolic acidosis
and respiratory alkalosis
• Lactates, ketones and
salicylates
– Acidemia – decompensate
and dying
• pH < 7.4 – poor prognostic
maker
pH
PCO2 HCOmmHG mmol/L
Early
7.5
30
24
Later
7.4
30
20
Dying
7.3
45
20
Dying
7.3
30
16
Clinical Manifestation
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GI - Vomiting
Pulmonary – ALI
CVS – Tachycardia
Hyperthermia
Sweating
Hypokalemia
Glucose
Diagnosis & Severity assessment
• History
– >150mg/kg
• Clinical manifestation - most important !
– Subtle in chronic poisoning (30% misdiagnosis)
• FeCl3 test
• ABG, electrolytes, urinalysis
• Drug level
– Therapeutic 15-30mg/dl
– Serum Salicylates (mg/dL)=13.8x serum
salicylates (mmol/L)
– Serial trend
Done Nomogram
• Limitation
– Assume all cases had
a same pH
– Clinically NOT useful
Management
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GI decontamination
ABC
Alkalinization
Extracorporeal removal
GI decontamination
• Gastric lavage
– Acute large overdose
– Spontaneous vomiting is common
• Multiple dose activated charcoal
– Reduce delayed absorption
• Whole Bowel Irrigation for
enteric coated tablets
ABC
• DO NOT allow
respiratory acidosis
during and following
intubation
• Kill the patient quickly
• DO give aggressive
volume resuscitation
• Hypovolemia
–
–
–
–
Vomiting
Sweating
Fever
Hyperpnea
ABC
• Monitor blood glucose and correct
hypoglycaemia
• Maintain a high normal blood glucose
• Maintenance IV Fluid: 1L D5
40 mmol KCL
3 amp of NaHCO3
• Adjust infusion rate and concentration
• Monitor urine output, serum/urine pH and serum
K level
Alkalinization
• Aim for both serum & urine alkalinization
• Indications
– Clinical Salicylism
– Level > 40mg/dl
• NaHCO3
– Bolus 1-2mEq/kg
– Maintenance
• Goal
– Urine pH 7.5-8
– Serum pH 7.45-7.55
• K+ is important for success
Extracorporeal removal
• Indications
– Vital end-organs toxicity
– Failure of excretion
– Failure of conservative
management
– Level
• Acute > 100mg/dl
• Chronic >60mg/dl
• Methods
– Hemodialysis
– Charcoal hemoperfusion
– Hemodialysis in series with
hemoperfusion
– Exchange transfusion in
infants
Are you going to manage this case?
• F20, Ingested 1 pack of
Cortal® 3 hours ago
• C/O Nausea, otherwise
asymptomatic
• Amount of ingestion
(Assume 50kg): 200mg/kg
• Range of mild to moderate
toxicity
Summary - Aspirin
• Another common overdose
• Understand the pharmacokinetic
• Recognize the clinical manifestation
and how to assess the severity
• Nomogram NOT useful clinically
• Don’t allow acidemia
• Treatment options available
and their indications
Thank you !
Dinner time