paracetamol and aspirin poisoning dr. sh tsui 23 march 2005
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Paracetamol and Aspirin Paracetamol and Aspirin PoisoningPoisoning
Dr. SH TsuiDr. SH Tsui
23 March 200523 March 2005
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ParacetamolParacetamol
• Very Common– 1054 registered pharmaceuticals
contain paracetamol in HK
• Perceived to be benign– But it can be lethal
• Treatable– Early antidote
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Poisoning DataPoisoning 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%
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QMH dataQMH data
• 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
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Who will manage this case in Who will manage this case in A&E/Observation ward?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 896mol/L, LFT normal
Who will continue to manage?
Who will start NAC?• Who will give full course of NAC in their O ward?
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PharmacokineticsPharmacokinetics
• Potential toxic dose– >150mg/kg
• Rapid absorption– Peak within 1-2 hour
• Vd – 1L/kg
• T1/2
– 2-3 hours, – Increased in overdose
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Metabolism Metabolism
• Non toxic metabolites– Sulfate conjugate– Glucuronide conjugate
• Toxic metabolites– NAPQI
• Determinants– Dose– P450 activity– 2E1 – polymorphism
results in different susceptibility
– Glutathione
APAPSulfateGlucuronide
>90%
Urine (unchanged)
cytochromeP450 (IIE1, IA2, IIIA4)
NAPQIGlutathione depletedGlutathione
Mercapturic acid conjugates
Cell Damage
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Liver toxicityLiver toxicity
• Central zone– Highest
concentration of P450
– Lowest oxygen content
• Massive centrilobular necrosis
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Risk factors for liver toxicityRisk factors for liver toxicity
• Enzyme induction: smoking, barbituates, phentoin, isoniazids, ethanol
• Decreased glutathione store: malnutrition-alcoholism, HIV, chronic illness
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Renal toxicityRenal toxicity
– Consistent with acute tubular necrosis
– P 450 in kidney
– NAPQI formation– Not hepato-renal
initially
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In massive overdoseIn massive overdose
• CNS– Coma – P450 in brain, ? Mechanism
• Metabolic– Metabolic acidosis, mitochondria dysfunction
• Coagulopathy– Directly interfere with coagulation factors– Later 2o to liver failure
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Clinical PresentationClinical 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
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Must Screen LevelMust Screen Level
• Paracetamol level– Approximately 1/500 poisoned cases
where there is no history of paracetamol overdose has a level requiring therapy
– Cost effectiveAshbourne: Ann Emerg Med 1989:18:1035
Kulig: Ann Emerg Med 1985;14:562
Sporer KA, Am J Emerg Med.1996;14:443-6
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TreatmentTreatment
• GI decontamination• Antidote• Liver failure
– Supportive– Transplant
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GI decontaminationGI 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
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Natural History of Untreated OverdoseNatural History of Untreated Overdose
Mortality < 5%
Hepatic failure 5-10%
Clinical hepatitis 20-40%
Chemical hepatitis 50-70%
Renal failure 10%
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Efficacy of NACEfficacy 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
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Antidote : N-acetylcystecineAntidote : 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
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Antidote : N-acetylcystecineAntidote : 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 outputHarrison: N Engl J Med
1991;324:1852
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Indications for NAC TherapyIndications for NAC Therapy
– Level available < 8 hours• Wait for level• Treat if above nomogram
– Level not available < 8 hours post ingestion • Treat first• Make decision to continue or stop therapy based on level
– Late Presentation (>24 hrs post-ingestion)• Detectable paracetamol level• Elevated AST
– Fulminant liver failure
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NomogramNomogram
• Paracetamol (g/ml) = 0.15 x Paracetamol (mol/L)
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Drawbacks of NormogramDrawbacks 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
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IV NAC doseIV 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 effectAnaphylactoid reactionRash, utricaria, bronchospasm, hypotension
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Treatment of liver failureTreatment 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
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Predictors of death in Paracetamol Predictors of death in Paracetamol liver failureliver failure
• Kings College’s criteria• pH < 7.30 after volume
resuscitation OR • Combination of 3 parameters
– Stage III or IV encephthalopathy– PT > 100 seconds– Creatinine above 300µmol/L
O’Grady: Gastroenterology 1989:97:439
• Newer Predictors– Lactate– Phosphate
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Extended Release PreparationsExtended Release Preparations
• First marketed in 1994
• Bilayered preparation contains ~650mg of paracetamol
• Delayed dissolution and release of half of the drug
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Observations from case reportsObservations 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
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RecommendationsRecommendations
• 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
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How about Fast Acting How about Fast Acting Paracetamol?Paracetamol?
• Paracetamol & sodium bicarbonate
• Doubles the absorption rates
• Syrup panadol overdose (Also fast absorption)
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Repeated Supra-therapeutic Repeated Supra-therapeutic intakeintake
• >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
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Summary – ParacetamolSummary – Paracetamol
• 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
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SalicylatesSalicylates
• 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
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PharmacokineticsPharmacokinetics
• Absorption– Tablets dissolution is the rate
determining step– Formation of concretion– Pyloric spasm– Significant dermal absorption,
especially in diseased skinBrubacher 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
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pH effectpH effect
• Acidemia • pH in serum lower than that of CSF
• Alkalemia • pH of serum higher than that of CSF
• HA Can cross membrane
• H+ A- Cannot cross membrane
pH ↑ pH ↓
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Metabolism & ExcretionMetabolism & Excretion
• Therapeutic– Hepatic conjugation with glucuronic acid or
glycine– Renal elimination insignificant
• Overdose– Hepatic conjugation saturated– Renal elimination become important
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PathophysiologyPathophysiology
• Uncouple the oxidative phosphorylation– Short circuit the
mitochondria membrane potential
– Generate heat instead
• Inhibits dehydrogenase in Kreb’s cycle
HA
H+A-
X
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Clinical ManifestationClinical Manifestation
CNS – Tinnitus or hearing
impairment – Confusion, lethargy,
coma, seizure– Cerebral edema– Death
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Clinical ManifestationClinical 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 mmHG
HCO- mmol/L
Early 7.5 30 24
Later 7.4 30 20
Dying 7.3 45 20
Dying 7.3 30 16
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Clinical ManifestationClinical Manifestation
• GI - Vomiting• Pulmonary – ALI • CVS – Tachycardia• Hyperthermia• Sweating• Hypokalemia• Glucose
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Diagnosis & Severity assessmentDiagnosis & 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
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Done NomogramDone Nomogram
• Limitation– Assume all cases had
a same pH – Clinically NOT useful
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ManagementManagement
• GI decontamination
• ABC
• Alkalinization
• Extracorporeal removal
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GI decontaminationGI decontamination
• Gastric lavage– Acute large overdose– Spontaneous vomiting is common
• Multiple dose activated charcoal– Reduce delayed absorption
• Whole Bowel Irrigation for enteric coated tablets
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ABCABC• DO NOT allow
respiratory acidosis during and following intubation
• Kill the patient quickly
• DO give aggressive volume resuscitation
• Hypovolemia– Vomiting– Sweating– Fever– Hyperpnea
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ABCABC
• 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
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AlkalinizationAlkalinization• 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
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Extracorporeal removalExtracorporeal 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
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Are you going to manage this Are you going to manage this case?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
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Summary - AspirinSummary - 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
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Thank you !Thank you !
Dinner timeDinner time