Paracetamol and Aspirin Paracetamol and Aspirin PoisoningPoisoning

Dr. SH TsuiDr. SH Tsui

23 March 200523 March 2005

ParacetamolParacetamol

• Very Common– 1054 registered pharmaceuticals

contain paracetamol in HK

• Perceived to be benign– But it can be lethal

• Treatable– Early antidote

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%

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

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?

PharmacokineticsPharmacokinetics

• Potential toxic dose– >150mg/kg

• Rapid absorption– Peak within 1-2 hour

• Vd – 1L/kg

• T1/2

– 2-3 hours, – Increased in overdose

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

Liver toxicityLiver toxicity

• Central zone– Highest

concentration of P450

– Lowest oxygen content

• Massive centrilobular necrosis

Risk factors for liver toxicityRisk factors for liver toxicity

• Enzyme induction: smoking, barbituates, phentoin, isoniazids, ethanol

• Decreased glutathione store: malnutrition-alcoholism, HIV, chronic illness

Renal toxicityRenal toxicity

– Consistent with acute tubular necrosis

– P 450 in kidney

– NAPQI formation– Not hepato-renal

initially

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

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

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

TreatmentTreatment

• GI decontamination• Antidote• Liver failure

– Supportive– Transplant

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

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%

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

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

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

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

NomogramNomogram

• Paracetamol (g/ml) = 0.15 x Paracetamol (mol/L)

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

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

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

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

Extended Release PreparationsExtended Release Preparations

• First marketed in 1994

• Bilayered preparation contains ~650mg of paracetamol

• Delayed dissolution and release of half of the drug

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

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

How about Fast Acting How about Fast Acting Paracetamol?Paracetamol?

• Paracetamol & sodium bicarbonate

• Doubles the absorption rates

• Syrup panadol overdose (Also fast absorption)

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

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

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

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

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 ↓

Metabolism & ExcretionMetabolism & Excretion

• Therapeutic– Hepatic conjugation with glucuronic acid or

glycine– Renal elimination insignificant

• Overdose– Hepatic conjugation saturated– Renal elimination become important

PathophysiologyPathophysiology

• Uncouple the oxidative phosphorylation– Short circuit the

mitochondria membrane potential

– Generate heat instead

• Inhibits dehydrogenase in Kreb’s cycle

HA

H+A-

X

Clinical ManifestationClinical Manifestation

CNS – Tinnitus or hearing

impairment – Confusion, lethargy,

coma, seizure– Cerebral edema– Death

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

Clinical ManifestationClinical Manifestation

• GI - Vomiting• Pulmonary – ALI • CVS – Tachycardia• Hyperthermia• Sweating• Hypokalemia• Glucose

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

Done NomogramDone Nomogram

• Limitation– Assume all cases had

a same pH – Clinically NOT useful

ManagementManagement

• GI decontamination

• ABC

• Alkalinization

• Extracorporeal removal

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

ABCABC• DO NOT allow

respiratory acidosis during and following intubation

• Kill the patient quickly

• DO give aggressive volume resuscitation

• Hypovolemia– Vomiting– Sweating– Fever– Hyperpnea

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

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

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

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

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

Thank you !Thank you !

Dinner timeDinner time