Paracetamol overdose

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Paracetamol overdose By Dr. opeoluwa folorunsho

Transcript of Paracetamol overdose

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Paracetamol overdose

By Dr. opeoluwa folorunsho

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Case

• EP a 34 year old British national • presented to the accident and emergency • 30 minutes after ingestion of approximately

100 tablets of acetimophen tablets • EP admitted to taking medication with

alcoholic wine

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Case

• had only been in Barbados for 2 days prior to ingestion

• suspicion of infidelity on the part of her boyfriend of 3 months who resides in the island.

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• one episode of clear colour vomitus• she denied :• abdominal pain• Headache• bleeding from any orifice• visual or auditory disturbances

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• it was her second attempt to terminate her life

• 1st attempt was 15 years ago (medication)• recently started seeing a psychologist for

depression• Currently not on any medication

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• As regards this episode• Felt disappointed that she was unsuccessful• Was not planning to do it again• She didn’t write a suicide note• called her boyfriend after ingesting the tablets

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Vitals on arrival

• Temperature………………….36.2 degree celcius• Blood pressure …………………..133/77 mmHg• Pulse …………………………….138 beats/min• Respiratory rate …………………22 cycles/ min• Oxygen saturation …….98 percent on room air

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examination

• young lady now in no apparent cardiovascular or respiratory distress

• Her membranes were pink and moist• she was anicteric and acyanosed• equal chest rise on inspection• vesicular breath sounds with no added sounds

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examination

• Her jugular venous pressure was not elevated and no distended neck veins observed

• Her pulse rate was 104 and regular with good volume

• First and second heart sounds noted with no murmurs or additional sounds appreciated

• Apex was at the 5th intercostal space mid clavicular line

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examination

• . Examination of the abdomen revealed a flat soft abdomen that moved with respiration

• No previous surgical scars or hernia cough impulse observed

• Liver was not enlarged or tender and there were no palpably enlarged organs

• Her bowel sounds were normal

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• No focal deficits observed and patient had equal and reactive pupils

• the rest of her central nervous system examination was essentially normal

• Her mood was “sad” and affect was downcast and tearful

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Case

• Speech rate was normal rate, rhythm, volume and tone

• EP denied thought insertion, withdrawal, broadcasting or flight of ideas

• She denied having suicidal or homicidal thoughts in the department and her risk for suicide score assessed her as medium risk of suicide

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Case

• having positive points for depression, previous attempt, ethanol use, rational thinking loss and organized plan using the SADPERSONS score

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• Patient was given 50g of activated charcoal orally 7,700mg of N-Acetylcystine based on her measured weight of 55.5kg (140mg/kg) in 500 mls of carbonated drink over one hour.

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• Patient was subsequently referred to both the internal medicine service and psychiatry.

• Admitted to under the internal medicine service

• continued her N- Acetylcystine at 4.5g every 4hrly with a total of 17 doses and to get serial liver function test done while on the ward

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Labs

Full blood count value Normal range

Hemoglobin(hbc)

White blood count(wbc)

Mean corpuscular volume(mcv)

Platelets(plt)

Hematocrit(hct)

12.6

6.1

87.7

413

38

13-18g/dL

4-11 K/uL

76-96 fL

150-400 K/uL

40-54 %

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Urea and electrolyte value Normal range

Sodium(Na)

Potassium (K)

Chloride (Cl)

Bicarbonate (CO²)

Urea

Creatinine (creat)

Bilirubin total(bili-t)

Alkaline phosphatase(Alp)

Alanine transaminase(Alt)

Aspartate Aminotransferase (AST)

139

3.9

101

17.3

1.4

53

5

52

15.4

26.8

138-144 mmol/L

3.1-4.1 mmol/L

101-107mmol/L

22-29 mmol/L

2.6-6.5mmol/L

68-126 umol/L

6-22 umol/L

39-106 IU/L

3-35 IU/L

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Day 1

• Patient however developed abdominal pain which she described as cramping in nature associated with vomiting of ingested meal

• loose stools which were dark yellow • she continued her N Acetylcystine but only

had 12 of the 17 recommended doses

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Case

• she self-discharged after 3 days of admission to return to the united kingdom to continue her management

• She did have normal liver function test in those 3 days of admission.

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Paracetamol overdose

• Paracetamol or N-acetyl-p-aminophenol is a common antipyretic and analgesic that has been used since the 17th century

• it is especially effective for the management of mild to moderate myalgia especially in patients who cannot take aspirin because of underlying bleeding or coagulation disorder

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• It is also the most widely available over the counter analgesic/antipyretic in the world

• single most commonly taken drug in overdoses that lead to hospital presentation and admission worldwide.

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• Absorption of paracetamol is largely at the small intestine where more than 80 percent of the drug after undergoing first pass metabolism in the liver

• Three mechanisms have been identified

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• 40percent to 60 percent of the ingested paracetamol undergo glucuronidation

• 20 percent undergo sulphonation• 15 percent undergo N-hydroxylation and

rearrangement with cytochrome P450 enzymes

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• All three processes result in the production of toxic and non toxic products

• The non-toxic products eventually excreted by the kidneys

• toxic product N-acetyl-P-benzoquinoneimine (NAPQI) undergo detoxification by glutathione and is eliminated in urine or bile

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• In cases overdose sulphate and glucuronide conjugation can be saturated

• accumulation of NAPQI and subsequent saturation and eventual depletion of glutathione

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• NAPQI that is not detoxified then reacts with sulphydryl groups on hepatocytes leading to hepatocellular necrosis

• A minimum single dose of 150 mg/kg may be associated with Hepatocellular damage

• EP took 100 tablets of 500 mg each which would amount to 27,750 mg. At a dose of 150mg/kg which would amount to 8,325 mg

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• Children however are less likely to have paracetamol toxicity even if amount consumed exceeds 150mg/kg because they have more active oxidative pathway, resulting in an increased rate of glutathione production, thereby conferring a protective effect from hepatotoxicity in young children

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• Paracetamol toxicity occurs in 4 different phase of presentation

• Summarised in the next slide

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Phase Expected day Symptoms/signs Expected

laboratory

changes

I first 24 hours Asymptomatic,anorexia

Nausea, vomiting, malaise,

pallor and diaphoresis

Maybe normal

II 24-48 hours

after ingestion)

Phase I plus right upper

quadrant pain,hepatomegaly,

oliguria

Liver enzymes

and bilirubin

may be elevated

III 72-120 hrs after

ingestion

Phase I,II plus

hypoglycemia,signs of

hepatic

failure,jaundice,coagulopathy

Low blood

glucose,

deranged liver

function, urea

and electrolytes

IV six days to two

weeks

central nervous system

depression,shock,

hypothermia, metabolic

acidosis, hypoglycaemia,

convulsions and pulmonary

edema

Same as phase

III

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• EP came to the accident and emergency on day one of her ingestion, actually within the hour after ingestion and she was asymptomatic

• however on day 1 of admission she developed abdominal pain and vomiting

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case

• In centers where available, Serum paracetamol concentrations should be measured in any patient who admits to taking excess paracetamol

• Prothrombin ratio (PTR) is the most sensitive marker of ensuing liver dysfunction in paracetamol poisoning; it becomes elevated at 18 – 24 hours after significant ingestion.

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• In certain centers a Nomogram to determine the likelihood of developing hepatotoxicity based upon plasma paracetamol levels can be obtained. Nomogram cannot be applied if the exact time of ingestion is unknown

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Nomogram

plasma or serum acetimophen concentration versus time post ingestion

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• Management of paracetamol toxicity involve the basics of life support which is to protect airway, breathing and circulation

• . This might be necessary especially in patients with multiple drug ingestion

• Paracetamol ingested as single drug rarely causes airway compromise

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Case

• However this also is dependent on the phase of presentation, most patients would usually present in phase I

• Activated charcoal can be given at a dose of 1g/kg but its efficacy in paracetamol toxicity is yet to be established

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Case

• Administer activated charcoal (AC) if the patient is alert and presents

• Ideally, within 1 hour post ingestion • Can be extended if the patient ingested an

acetaminophen-based sustained-release medication or if the ingestion includes agents that are known to slow gastric emptying

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Case

• More important than gastrointestinal decontamination after paracetamol ingestion is the early administration of N-Acetylcysteine

• It is 100% hepatoprotective when it is given within 8 hours after acute acetaminophen ingestion

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Case

• N-Acetylcysteine is composed of amino acid L-cysteine with an acetyl molecule attached. The former is responsible for the production of glutathione in cells and also controls production

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• Acetylcysteine should be administered by intravenous infusion preferably using Glucose 5% as the infusion fluid. Sodium Chloride 0.9% solution may be used if Glucose 5% is not suitable

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• .The full course of treatment with acetylcysteine comprises of 3 consecutive intravenous infusions. Doses should be administered sequentially with no break between the infusions. The patient should receive a total dose of 300 mg/kg body weight over a 21 hour period

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Case

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• N-Acetyl cysteine carries the risk of anaphylactoid reaction like flushing, pruritus, rash bronchospasm and hypotension (< 2% of patients)

• Stopping the infusion, administering an antihistamine, and restarting N-Acetyl cysteine at a slower infusion rate is recommended.

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• Oral formulation of N-Acetyl cysteine (Mucomyst) can also be used for the treatment of acetaminophen overdose

the route of choice and gastric decontamination with activated charcoal prior to starting N-Acetyl cysteine therapy does not change the therapeutic schedule for treatment

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• The approved dosage regimen for oral form starts with a loading dose of 140 mg/kg, followed by 17 doses, each at 70 mg/kg, given every 4 hours. The total duration of the treatment course is 72 hours

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• In centers were N-acetylcysteine is not available, methionine can be used (12 g orally 4-hourly, to a total of four doses) it is an essential amino acid and an intermediate in the biosynthesis of cysteine

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• It is useful in paracetamol overdose because it stimulates the production of gluthatoine and prevents hepatic dysfunction

• Some argument in favour of methionine that it carries less adverse effects when compared with N-Acetylcysteine

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• Some countries are advocating preparing paracetamol with methionine which is then converted into glutathione in the liver

• In chronic ingestion of paracetamol, N-Acetyl cysteine can be commenced if the liver function tests are deranged or persistently elevated serum or plasma paracetamol concentration when available.

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Conclusion

• Paracetamol toxicity is a common presentation in the accident and emergency and accurate history is essential in particular to the amount and time of ingestion.

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• The availability of N- Acetylcysteine in the intravenous form would be a added advantage, the patient in this case sighted the not so pleasant taste of the oral form of the medication despite taking it with carbonated soft drink as one of the reasons for discharging against medical advice

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References

• 1. Buckley N, Eddleston M. Paracetamol (acetaminophen) poisoning. Clin Evid 2005; (14): 1738-1744.

• 2. Borne, Ronald F. "Nonsteroidal Anti-inflammatory Drugs" in Principles of Medicinal Chemistry, Fourth Edition. Eds. Foye, William O.; Lemke, Thomas L.; Williams, David A. Published by Williams & Wilkins, 1995. p. 544–545

• 3. Mehta, Sweety (August 25, 2012) Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin. pharmaxchange.info

• 4. Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (2008). "Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres". Med J Aust 188 (5): 296–301. PMID 18312195.

• 5. Rumack B, Matthew H (1975). "Acetaminophen poisoning and toxicity". Pediatrics 55 (6): 871–76. PMID 1134886

• 6. Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database. Curr Med Res Opin. Oct 2007;23(10):2359-68. [Medline].

• 7. Wolf SJ, Heard K, Sloan EP, Jagoda AS. Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose. Ann Emerg Med. Sep 2007;50(3):292-313.

• 8. Blackford MG, Felter T, Gothard MD, Reed MD. Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: a retrospective review. Clin Ther. Sep 2011;33(9):1322-30.

• 9. McNeil Consumer and Specialty Pharmaceuticals. Guidelines for the Management of Acetaminophen Overdose. Available at http://www.tylenolprofessional.com/assets/Overdose_Monograph.pdf. Accessed July 11, 2013

• 10. "Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine". Drug Safety Update (Medicines and Healthcare Products Regulatory Agency (MHRA)) 6 (2): A1. September 2012