This document provides an overview of paracetamol (acetaminophen) including its history, epidemiology, pathophysiology, clinical presentation, management, and N-Acetyl Cysteine (NAC) treatment protocol for overdose. It describes paracetamol as a commonly involved drug in overdose cases that can cause severe liver damage if taken in high enough quantities. The management of paracetamol overdose involves evaluation to determine risk of hepatotoxicity and administration of NAC, an antidote, to prevent liver injury.

1. Paracetamol Overdose in
Adults.
Ghassan Al Kefeiri
Eastbourne District General Hospital
A&E
June, 2020

2.  History of Paracetamol.
 Epidemiology.
 Pathophysiology.
 Clinical presentation.
 Management.
Overview:

3.  Paracetamol was first used clinically by Von Mering in 1893,
appeared commercially on 1950 in USA and Australia with
extreme safe record. 5
 During 1960s and 1970s, concerns were raised about toxicity of
OTC analgesics.
 1966 discovery that major overdose of paracetamol could be
complicated by severe, sometimes fatal, liver damage.
 1980 was the turning point where Paracetamol started being
widely used in Paeds after linking Aspirin to Reye’s Syndrome
History:

4.  Acetaminophen.
 APAP ( N-Acetyl-P-Aminophenol).
Synonyms:

5.  Comes either alone or in combination with other
agents:
Trade names:
• Panadol
• Tylenol ( North America)
• Panadol Extra
• Solpadiene
• Calpol
• Paracetamol
• Migraleve
• Sinutab
• Syndol
• Anadin
• Lemsip
• Beechams
• Co-codamol

6.  Tablets 500mg or 1gm.
 Caplet 500mg.
 Capsules 500mg.
 Effervescent tablet 500mg.
 Soluble tablet 500mg.
 Orodispersible tablet 250mg.
 Oral suspension 120mg/5ml, 250mg/5ml, 500mg/ml.
 Solution for infusion 100mg/10ml, 500mg/50ml, 1g/100ml.
 Suppository 60,80,120,125,240,250,500mg & 1gm.
 Powder in cold relief formulas 650mg.
Formulas: 11

7.  Frequently involved in cases of poisoning and estimated to account
for over 40% of all self poisoning cases presenting to hospitals in
England. 1-2
 Approximately 200-250 Deaths/yr in England and Wales. 3
 In 2018 Paracetamol comprised to 210 Deaths in England and Wales. 4
 Accidental overdose patiets had a higher rates of severe
hepatotoxicity, Hepatic coma and Death compared to those who
attempted suicide though the latter had more paracetamol. 6
 Annually 30.000-40.000 cases of paracetamol overdose present to
A&E. comprsong 48% of admission for self-poisoning, 10% requires
Antidote. 7
Epidemiology:

8.  Self Harm
 Iatrogenic:
 Inadequate explanation of directions to use.
 Over administration in wards and care homes.
 Failure to recognize that Paracetamol is found in more than one
medication and not explaining that to patient.
 Pattern of use:
 Repeated supratherapeutic dose where patient ingest a high dose in
attempt to relief pain or for fever. Such patients might be either fasting or
chronic alcoholics and more likely to present to medical care late when
toxic effects are already established.
 Repeated therapeutic doses which results in mild, self-limiting, clinically
insignificant transaminase elevation ( ALT).
Causes:

9.  Paracetamol is absorbed completely at the duodenum.
 Peak serum concentration at 1-2 hours post ingestion.
 Peak plasma levels at 4 hours post ingestion of an immediate
release formula.
 Drugs that delays gastric emptying, or extended release
formulas, will prolong peak serum levels for up to 8 hours.
 Elimination half-life is between 0.9-4 hours and it can get up to
17 hours if there is an underlying hepatic dysfunction.
Pathophysiology:

10.  Paracetamol is metabolized by conjugation in liver to a nontoxic,
water-soluble compound which is finally excreted in urine.
 In overdose, conjugation becomes saturated and excess
paracetamol is oxidatively metabolized by CY enzymes ( 2E1, 1A2,
2A6, 3A4) to produce the heapatotoxic NAPQi (N-Acetyl-P-
Benzoquinoneimine)
 NAPQi has a short half life and is rapidly conjugated to Glutathione
and excreted in urine
 Toxicity appears when NAPQi is excessively produced or when
Glutathion is reduced to 70%.

11.  NAPQi covalently binds to cesteniyl sulfhydryl groups
of hepatocellular protein ( particularly mitochondrial)
to form NAPQi protein products, an irreversible
product, resulting in a cascade of oxidative
hepatocyte injury, mitochondrial dysfunction,
alteration to mitochondrial ATP-synthase alpha and
centrilobular hepatocellular necrosis.

12. 8

13.  Minimum toxic dose for a single ingestion:
 7.5-10 gm in Adult 15-20 tablets of 500 mg Paracetamol.
 150 mg/kg -200 mg/kg in children 1-6 years of age.
 Clinical manifestations of hepatotoxicity do not manifest until
24-48 hours post ingestion.
 There is no early clinical symptoms that would predict toxicity.
So assessment on early stages in mainly achieved through a
proper history ( Time, amount and formula of ingestion) and
laboratory results.
Clinical Manifestations:

14.  Phase 1:
 Occurs 30 min to 24 hours post ingestion
 Ranging between asymptomatic to Anorexia, Malaise
and Nausea and Vomiting.
Clinical manifestation phases:

15.  Phase 2:
 18-72 hours post ingestion.
 Symptoms might initially improve during this stage.
 Patient might complain of RUQ pain and tenderness,
anorexia, nausea, vomiting.
 Tachycardia and hypotension reflects volume depletion.
 Some patients might have oliguria.

16.  Phase 3:
 72-96 hours post ingestion.
 Same clinical manifestations of phase 2.
 Signs of hepatic necrosis or dysfunction: jaundice, hypoglycaemia,
hepatic coagulopathy, lactic acidosis, hyperammonemia, total
bilirubin >4.0 mg/dl and hepatic encephalopathy.
 AKI in some severely ill patients.
 Death due to multiorgan failure.

17.  Phase 4:
 The recovery phase
 Lasts between 4 days to 3-4 weeks for those who
survive phase 3.

18.  Acute Markers:
 INR
 PT
 Lactate
 Aminotransferases ( >3000 iu/l)
 RFT
 LVT ( AST:ALT > 2 in chronic use)
 Paracetamol level is best taken at 4 hour post ingestion if
time is known or immediately at presentation if not.
 BM
Investigations:

19.  Alcoholic hepatitis.
 Other drug or toxin induced hepatitis.
 Viral hepatitis (total Bilirubin >1mg/dl).
 Hepatobiliary disease.
 Reye’s Syndrome.
 Ischemic hepatitis.
Differential diagnosis:

20.  Immediate release preparations:
 There is no correlation between the amount of paracetamol
ingested or serum concentration measured i.e dose history does
not predict hepatotoxicity.
 If timing is unclear, paracetamol level immediately and repeat after
4 hours.
 If initial paracetamol levels is normal, patient must stay under
observation for 4 hours.
 If initial level in undetectable, the decision on weather to give NAC
or not is based on presence of absence of lab indicators of
hepatotoxicity. If in doubt, start NAC.
 Unknown time or > 8hrs, start NAC immediately before lab results.
Evaluation of Acute Ingestion:

21.  Sustained release formulas:
 No sufficient experience to know weather Rumack-
Matthew nomogram can assess risk.
 It is recommended to measure paracetamol levels at 4
and 8 hours post ingestion.
 Start NAC at the first high reading.

22.  Repeated supratherapeutic ingestion:
 Requires more in-depth history ( dose, pattern of use etc..)
 Clinical manifestations are insidious in onset, often non-specific and
easily confused with alternate diagnosis.
 Paracetamol levels are always high and do not correlate with
hepatotoxicity as with the acute presentation.
 Requires assessment of hepatic toxicity risk

23.  Assessment of hepatotoxicity risk:
 Patient is at an increased risk if history, clinical and lab data are
positive plus any of the following:
 >7.5 g over 24 hrs + chronic alcohol, malnourished, drugs that increase
CYP450 activity.
 Abdominal pain, liver tenderness, nausia, vomiting, jaundice or patient
is ill appearing.
 Detectable paracetamol levels (above treatment line) with or without
increase in ALT.
 increased ALT >50 u/l with history of paracetamol ingestion regardless
paracetamol levels.
 Hepatotoxicity ALT >1000 u/l while acute liver injury ALT >50 u/l

24.  Elevated paracetamol-Aminotransferase
multiplication product:
 On presentation, it predicts hepatotoxicity regardless
time.
 (Paracetamol level × ALT)
 Sensitivity of 100% however, drops to 54% at 8 hours.
 Cut-off point is 10.000 where above is hepatotoxicity
and below is not.

25. • Used at 4 hours
• Not useful after 24 hours
• Not useful for sustained release
formulas.
• Treatment line is actually 25% lower
than the actual line as a safety margin
which protects susceptible patients
who are at high risk of developing
hepatotoxicity.
Modified Rumack-Matthew
nomogram

26.  G.I decontamination:
 Activated charcoal (AC)at 1 gm/kg ( maximum of 50 gm) p.o within
the first four hours of ingestion.
 AC should not be given to patients who cannot maintain their
airway.
 It was found that patients are less likely to develop liver injury if AC
was given before NAC. 6
 One study found that those who had AC in the first 2 hours had no
need to take NAC. 6
 One study suggested administration of AC post 4 hours may be
beneficial. 6
Management:

27.  Is theorized to work through different mechanisms
 It is a precursor of Glutathione.
 Enhance sulfate conjugation of unmetabolized paracetamol.
 Function as anti-inflammatory and Antioxidant.
 Has positive inotropic effect
 Increase local nitric oxide.
 Ideally given within the first 8 Hours of acute ingestion. However,
it should be given regardless time.
 It reduces mortality in late presenting patients with fulminant
hepatic failure even in the absence of measurable paracetamol
level.
N-Acetyl Cysteine (NAC):

28.  Indications:
 Serum paracetamol above treatment line.
 suspected ingestion of >/= 7.5 gm of paracetamol in patient who
serum paracetamol levels will not be available immediately or
delayed after 8 hours of ingestion.
 Unknown time of ingestion.
 History of ingestion and evidence of liver injury.
 Delayed presentation (> 24 hours) consisting of Lab evidence of
liver injury and history of excessive ingestion.
 Massive overdose requires larger dose of NAC. However, no
controlled studies demonstrated that increasing dose would
prevent liver injury.

29.  Administration:
 UK protocol was adopted on 1970 and still in use.
 20 hours I.V protocol as follows:
 Initial dose of 150 mg/kg I.V. over 15-60 min ( recommended 60 min-6-).
 Next 50 mg/kg over 4 hours.
 Finally 100 mg/kg over 16 hours.
 Effect of weight: current dosing protocols is calculated on maximum
body weight of 100 kg. However, there is no evidence that dose
calculated with body weight above 100 kg has provided added benefit. 6
 Dose based on actual body weight or estimated body weight is
acceptable. 6
 Consider antiemetic such as single dose Ondansetron 4-8 mg I.V. (6)

30.  Adverse reactions:
 Anaphylaxis:
 12-20% of patients develop hypersensitivity.
 It is warrant to keep close monitoring when giving NAC.
 There is limited evidence regarding continuation of NAC in patient
with anaphylaxis. Contact local poison control centre. 6

31.  Suggested approach with Anaphylaxis: 6
 Patient with flushing without pruritus: continue NAC unless severe
signs develop.
 Patient who develop Urticaria: Stop infusion immediately. Treat
with Epinephrine, Steroids, Antihistamine and Salbutamol if wheezy.
Restart infusion if patient improve.
 Patient who develop hypotension or persistent anaphylactic
symptoms: Stop NAC, treat anaphylaxis and DO NOT resume NAC.
Oral NAC should be provided. 6

32.  Oral Methionine is useful if: (8)
 Allergy to NAC.
 Difficulty obtaining or maintaining I.V line.
 Patient does not wish to stay at the hospital (DAMA).
 Awaiting plasma paracetamol concentration.
 Dose of 2.5 g initially followed by three further doses of 2.5 g
every 4 hours.
 Avoid if patient is vomiting or AC has been given

33.  When to stop NAC?
 For acute ingestion:
 When ALT is not elevated, INR <2.0 or ALT is acceptably decreasing
(consult your senior) stop at 20 hours.
 Check ALT at 18 hours, if still high or Paracetamol is still detectable,
continue treatment for 4 hours at 6.25 mg/kg/hr for 4 hours.
 For repeated ingestion, ALT is not elevated
 NAC for 12 hours
 Check ALT at 11 hours if high or paracetamol is detectable continue
6.25 mg/kg/hr for 12 hours.

34.  Alcohol:
 Acute ingestion: does not appear to be a risk factor for hepatotoxicity
and maybe protective as it competes with paracetamol for CYP2E1
resulting in reduced NAPQi
 Chronic ingestion:
 It appears to be no evidence of increased hepatotoxicity in chronic
alcoholics who take therapeutic dose of paracetamol. However, individual
factors vary. 6
 Single overdose: evidence suggest no increase risk compared to non-
alcoholics for developing hepatotoxicity. Management remains the same.
 Multiple overdose: Chronic alcoholics appears to be at increased risk of
hepatotoxicity. Risk factors include malnutrition, recent fasting and
depleted hepatic Glutathione.
Special conditions:

35.  Chronic liver disease:
 Patient with chronic liver disease who do not regularly ingest
alcohol do not appear to be at risk of hepatotoxicity.
 Note that paracetamol metabolism is reduced and half life is more
than 4 hours.
 More importantly, CYP450 is low and cannot be induced leading
to hepatic protection.
 It is generally recommended that no more than 2 g to be given in
24 hours.

36.  Isoniazide
 Rifampin
 Phenytoin
 Phenobarbital
 Barbiturates
 Co-Trimoxazole
 Opioids
 Zidovudine
 St.John’s Wort
 Garlic
 Germander
Medications& Herbs that increase activity of CYP450:

37.  Tobacco:
 It is an indepenmdant risk factor for mortality
depending on the amount. Mortality was higher in
smokers who also consume Alcohol.
 Cigarettes contain CYP1A2 inducers leading to increase
oxidative metabolism

38. Pregnancy:
 No difference on essential elements of treatment.
 Paracetamol can cause foetal and neonatal death from
hepatic necrosis.
 Treatment is indicated if Paracetamol >20 mcg/ml or
serum transaminases >50 u/l.
 It is likely that maternal toxicity would increase risk of
adverse pregnancy outcome. 6

39.  Outcome is nearly always good if NAC is given in timely
fashion.
 When fulminant hepatic failure and death occur?
 Usually from delays in seeking medical attention, recognition of
poisoning or delays in starting the appropriate therapy.
Prognosis

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regional teaching hospital in the UK. Br J Clin Pharmacol 2009;68:260–8
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ONS, 2011.
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evaluation
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References: