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TAPNA COURSE 2021

Lesson 5 – Paracetamol Summary

Mechanism of action

• Active metabolite of Phenacetin and Acetanilide

• Weak COX-1 and COX-2 inhibition in peripheral tissues

• Anti-nociceptive effects secondary to interaction with endogenous opioid, cannabinoid and

serotonin receptors.

Pharmacodynamics

• Analgesic (serum concentration 10mcg/ml) and Anti-pyretic (serum concentration 4-18mcg/ml).

• No significant anti-inflammatory, uric acid level modulating effects, platelet inhibiting effects.

Therapeutic Indications & Dose

• Simple analgesia (mild to moderate pain) and Pyrexia

• 15 mg/kg (Maximum 1g) QID (Maximum 4g per 24hr)

Formulations

• Liquid

o 24mg/ml, 48mg/ml, or 100mg/ml

• Immediate release

o 500mg per tablet. 125mg/250mg/500mg per suppository

o PO / IV / PR. Soluble / Capsule / Tablet

• Modified release

o 665 mg per tablet

o 69% modified release + 31% immediate release

• Combination (Paracetamol 500mg per tablet plus …)

o Moderate-Severe pain: Codeine 7.5 mg (Panadeine, Cold and flu tablets) or 15mg (Panadeine

forte), Ibuprofen (Nuromol), Tramadol 325mg (Zaldiar), Orphenadrine 35mg (Norgesic)

o Migraine: Doxylamine 12.5mg (Dolased), Caffeine 65mg (Panadol extra), Metoclopramide

10mg (Anagraine)

o Cold & Flu: Phenylephrine 5mg / Pseudoephedrine 30mg / Chlorpheniramine 2mg /

Dextromethorphan 15mg (Cold and flu tablets)

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Pharmacokinetics & Toxicokinetics

Absorption

• Readily absorbed by the oral route. Oral bioavailability 70-90%.

• Onset of action 5-10min (IV), 30-min (liquid), <60-min (oral).

• Tmax 45-min (PO, immediate release), 30-min (PO, liquid), 15-min (IV).

• Duration of action 4-6hr (PO, analgesia), >6hr (IV, anti-pyretic).

• Modified release: Prolonged absorption phase. Peak 2-3hr (may be delayed up to 20hr in overdose).

Distribution

• 10-15% protein bound (8-43% toxic concentrations)

• VD 0.9L/kg

Metabolism

• Hepatic metabolism

• Paracetamol > APAP-Glucoronide via Glucoronidation (40-67%) > Renal excretion

• Paracetamol > APAP-Sulfate via Sulfation (20-46%) > Renal Excretion

• Paracetamol > NAPQI via Oxidation (CYP 450 2E1) (5-15%) > Mercaptopuric acid + Cysteine via

Glutathione > Renal Excretion

Excretion

• <5% excreted unchanged in urine

T ½

• Elimination half-life 2-2.5 hr

• Unaffected by renal function

• Increased 2-fold toxic concentration (8hr)

and severe hepatic impairment

Adverse Effects with therapeutic doses

• Mild and reversible elevation in

aminotransferases

Precautions

• Pregnancy & Lactation Safe (Cat A).

• Severe hepatic impairment

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Paracetamol Poisoning

Overview

• Widely available and responsible for significant proportion of accidental and deliberate poisoning.

• Although it is commonly implicated in overdose, the risk of severe hepatic injury and death is low

due to the availability and effectiveness of NAC (survival 100% if administered within 8hr of

ingestion).

• APAP induced hepatic injury remains a major cause of fulminant liver failure in developed countries

due to delayed presentations.

• At therapeutic doses, small amounts of NAPQI, toxic metabolite, produced are detoxified by

irreversible glutathione-dependent conjugation reactions to two non-toxic metabolites. In overdose,

the sulfation pathway becomes saturated, and increased formation of NAPQI via the CYP2E! pathway

depletes Glutathione and once it is depleted by more than 2/3 it covalently bonds to hepatocytes

leading to hepatocyte injury and death.

Risk Assessment

Patient Factors

• Factors which increase the risk of hepatotoxicity include, glutathione depletion (e.g., starvation,

anorexia nervosa, known liver disease, cystic fibrosis), genetic pre-disposition, advanced age,

catabolic post op patients, children with febrile illness with excessive dosing.

• Co-morbidities and regular medications. CYP450 inducers increase NAPQI production e.g., Chronic

heavy Ethanol use, Rifampicin, Isoniazid, and theoretically Carbamazepine, Phenobarbitone and

Phenytoin.

• Children: Uncommon for children <6yo to develop toxicity. Most liquid ingestions are small,

accidental, and have prompt review, with NAC rarely being needed.

Drug Factors

• Acute single ingestion associated with acute liver injury: >10g or >200mg/kg (weight <50kg)

(whichever is less) within 24hr.

• Massive ingestion: >30g or >500mg/kg (weight <60kg) or greater than double the 150mg/l at 4hr.

• Very large overdose: >50g or >1g/kg or greater than triple the nomogram treatment line.

• Repeated supratherapeutic ingestion (RSTI): >10g or >200mg/kg (weight <50kg) (whichever is less)

over 24hr. >12g or >300mg/kg over 48hr. >4g or >60mg/kg >48hr + Symptoms of acute hepatic injury

(Abdominal pain, Nausea, Vomiting).

• Multiple/Staggered IR ingestions over >2hr: Separate to RSTI. Treated as per acute IR ingestion. Treat

the patient as if they took all their tablets at first (earliest) point i.e., 1300. If patient presents <8hr,

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use the <8hr guideline and time anchor

at 1300. If the first [APAP] was

measured within 2hr of the last ingested

paracetamol dose, it should be repeated

after 2hrs to ensure there is no ongoing

absorption. If either concentration is

above the nomogram line (using time

from the earliest ingestion), start or continue treatment with NAC. If patient presents 8-24hr, use the

8-24hr guideline and time anchor to first dose. Patient presents >24hr, treat as per acute ingestion

guidelines.

• Co-ingestants: Drugs which delay gastric emptying and prolong absorption e.g., anti-cholinergics,

opioids.

Clinical Features

• Phase 1 (<24-hr): Asymptomatic or nausea, vomiting and abdominal pain

• Phase 2 (24 – 72hr): RUQ pain, hepatic transaminitis. INR and APTT elevated and peak following peak

of AST/ALT. Elevated Bili if AKI.

• Phase 3 (72-96hr): Fulminant hepatic failure, hypoglycaemia, severe coagulopathy (PT

>100s), jaundice, hepatic encephalopathy, MODS (AMS, AKI), HAGMA (may be present in massive

ingestion acutely without liver failure), lactic acidosis, death.

• Phase 4 (>96hr): Recovery phase (hepatic structure and function return to normal).

Investigations

Baseline:

• ECG and HCG (females of childbearing age)

Paracetamol level:

• For immediate release formulations (single ingestion), obtain a timed [APAP] i.e., 4-16hr. Levels can

be plotted on the Rumack-Matthew nomogram to determine risk of hepatotoxicity, and guide

treatment with NAC. Limitations of nomogram; only applies to single acute immediate release

ingestion, does not apply to co-ingestants / modified release ingestions (case reports of line crossers),

not validated <4hr or >16hr, each country has different nomograms and units. Levels which are above

the nomogram line require treatment with standard 2-bag NAC regimen. [APAP] double or triple the

nomogram line require treatment with high dose NAC.

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• For modified release formulations, measure [APAP] every 4-6hr to check for ongoing paracetamol

absorption. Majority of APAP absorbed at 4hr and peak within 4hr, but a small portion of patients

may have an initial [APAP] below the nomogram line but have a subsequent [APAP] above

(nomogram crossing, also occurs with IR APAP and co-ingestion with anti-cholinergics and opioids

due to delayed absorption).

• For poisoning with liquid formulations (>200mg/kg) in children <6yo who present within 4hr of

ingestion, measure a 2hr [APAP], and if the 2-hr level >150mg/l, it should be remeasured at 4hr. If

the [APAP] >150mg/l, NAC should be commenced. In patients who present beyond 4-hr, or are >6yo,

manage as per immediate release APAP poisoning.

Liver function tests:

• AST: ALT <1 = Viral hepatitis, ischaemic necrosis, toxic hepatitis i.e., paracetamol.

• Aminotransferases in particular ALT help predict risk and determine severity of hepatotoxicity.

• ALT should be measured at presentation following APAP poisoning with immediate and modified

release formulations, and at regular intervals during NAC infusion.

Coagulation profile:

• INR may be slightly raised (no more than 2) early (4-24hr) due to APAP directly inhibiting clotting

factor production (VitK dependent factors II, VII, IX and X).

Other tests in patients with acute liver injury:

• VBG (pH and lactate), EUC (AKI), Glucose (hypoglycaemia), CMP.

Resuscitation & Supportive Care

• CNS and cardiorespiratory compromise secondary to APAP toxicity alone are unlikely to occur. Coma

and lactic acidosis can occur in massive overdoses, i.e., [APAP] >800mg/l, and delayed presentations

with hepatic failure.

• Detect and correct thermoregulatory dysregulation and metabolic/electrolyte disturbances.

GI Decontamination

• Following APAP supratherapeutic ingestion, AC 50g (1g/kg) should be offered to awake and

cooperative patients who are able to protect their airway within 2hr of ingestion (within 4hr if >30g

or >50mg/kg).

• AC should be offered to patients following supratherapeutic modified release formulations up to 4hr.

Consider repeated doses every 4hr if >30g or >500m/kg ingested, or serum paracetamol

concentration rising indicating ongoing absorption.

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• AC can be administered at any time following intubation and confirmation of NGT placement for

poisoning secondary to immediate and modified release paracetamol.

• AC should not be offered following liquid formulation supratherapeutic ingestion (absorption rapid

and complete within 30min of ingestion).

Antidote Administration – N-acetylcysteine (NAC)

Possible mechanisms of action:

• Increased glutathione availability, direct binding to NAPQI, provision of inorganic sulfate, reduction

of NAPQI back to Paracetamol.

• Almost completely protective against deaths secondary to Paracetamol induced hepatic injury when

administered within 8hr of ingestion (<1% develop severe hepatic injury).

Indications

• Supratherapeutic ingestion + Unknown time of ingestion (TOI) OR Serum concentration not available

within 8hr of ingestion. Cease infusion if [APAP] below treatment line and ALT <50IU and APAP not

ingested last 2hr, otherwise measure [APAP] and ALT again 2hr later.

• Supratherapeutic ingestion of immediate release + [APAP] available within 8hr of ingestion + [APAP]

on or above nomogram line.

• Supratherapeutic ingestion of immediate release + TOI 8-24hr. Infusion can be ceased if timed [APAP]

below treatment line + ALT <50IU.

• Supratherapeutic ingestion + TOI >24hr. Infusion can be ceased if [APAP] <10mg/l + ALT <50IU.

• Supratherapeutic ingestion of modified release paracetamol.

• Repeated supratherapeutic ingestion + ALT >50IU OR [APAP} >20mg/l OR Patient is symptomatic and

investigation results will be delayed >2hr after presentation. Can be stopped early if 0hr ALT <1000IU,

8hr ALT <50IU / static AND [APAP] <10mg/l.

• Accidental ingestion of liquid paracetamol >200 mg/kg in children <6yo + 4hr [APAP] >150mg/l.

Benefits:

• When administered within 8-hr of ingestion in APAP poisoning, risk of severe hepatic injury and

secondary death is extremely low.

• When administered between 8 and 15hr, risk of hepatic injury is low, however not as low compared

to administration within 8-hr.

• Beyond 15hr, there is no benefit regarding hepatic injury, however NAC decreases inotropic

requirements and cerebral oedema.

Adverse effects:

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• Mild elevation in INR as it interferes with PT assay (up to 1.3 if stable does not indicate start of hepatic

failure).

• Anaphylactoid / Non-IgE mediated anaphylactic reactions

o Urticaria, Bronchospasm, Nausea, Vomiting, Angioedema, Flushing, Tachycardia,

Hypotension, occurs in 10-50% cases

o Secondary to 2.5-fold increase histamine without elevated tryptase concentrations.

o More likely to occur in lower APAP ingestions as NAPQI appears to be protective, more likely

to occur with rapid administration of larger doses.

o High rates of non-IgE mediated reactions with the traditional 3-bag regimen has led to the

development of the SNAP protocol (12-hr regimen) and two-bag regimen, which are

associated with lower rates of severe reactions.

• Non-IgE mediated anaphylactic reaction management:

o For moderate-severe reactions, stop the infusion and give PO Loratadine 10mg.

o Recommence NAC once symptoms settle at half rate for 30-min then recommenced as per

normal protocol.

Dose: Two bag regimens

• Adult

o NAC 200mg/kg in NS 500ml over 4hr then

o NAC 100mg/kg in NS 1000ml over 16hr

• Child

o NAC 200mg/kg in NS 7ml/kg (max 500ml) over 4hr then

o NAC 100mg/kg in NS 14ml/kg (max 1000ml) over 16hr

• Massive ingestion or serum concentration double or triple the nomogram line

o NAC 200mg/kg in 500ml over 4hr then

o NAC 20mmg/kg in NS 1000 over 16hr

• Repeated supratherapeutic ingestion / unintentional poisoning

o Standard two bag regimen

o If ALT >1000IU, complete the 20hr infusion. If ALT <1000IU, remeasure ALT at 8hr, and

infusion can be ceased if ALT <50IU and [APAP] <10mg/l.

Monitoring and Ceasing infusion

• Patients on extended NAC therapy need regular clinical review and blood tests every 12hr.

• 2-hr before NAC 20hr infusion completion check

o Paracetamol level, ALT, INR, Clinical status

• Discontinue NAC 20hr infusion if

o Paracetamol level <10mg/l

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o ALT <50IU

o INR <2

o Clinically stable

• Continue NAC infusion

o If patient does not meet above criteria, i.e., NAC 100mg/kg in NS 1000ml for 16hr (adults) or

NAC 100mg/kg in NS 14ml/kg (max 1000ml) (children).

o Small fluctuations in ALT (e.g., +/- 20 U/L or +/-10%) are common and do not on their own

indicate the need for ongoing acetylcysteine.

Enhanced Elimination

• Not applicable

Disposition

Immediate release

• Patients who present within 8 hours of an acute ingestion of immediate-release paracetamol do not

need to be admitted if their initial [APAP] below treatment nomogram line.

Liquid formulation

• Children who present within 4 hrs of an acute ingestion of liquid paracetamol (>200mg/kg) do not

need to be admitted if their [APAP} measured 2-4 hrs after ingestion < 150 mg/L (1000 micromol/L).

• Children who present within 4hr of an acute ingestion <200mg/kg can be set home if well and

monitored for abdominal pain/N&V.

Modified release

• Patients do not need to be admitted to hospital if they fulfil the following criteria:

o They ingested less than 10 g (or 200 mg/kg in patients under 50 kg) of modified-release

paracetamol

o Two [APAP] taken 4 hr apart are below the treatment nomogram line, and the second

measurement is lower than the first.

General Advice

• Advise patient/carer to return to ED if they develop symptoms of acute liver injury (abdo pain, N&V).

• All patients with deliberate self-poisoning require psychiatric assessment before discharge. To

facilitate psychiatric assessment and treatment, if indicated, patients may require a longer period of

observation.

• Admit patients who are treated with acetylcysteine to hospital.

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Liver Failure and Referral to Transplant Unit

• Paracetamol overdose is the most common cause of fulminant hepatic failure in the USA (39% of

cases).

• Paracetamol-induced hepatotoxicity is defined as a peak elevation in hepatic transaminases (ALT or

AST) > 1000 IU/L in the context of paracetamol overdose. Only a small proportion of patients develop

hepatotoxicity (ALT >1000IU).

• Liver transplantation increases survival in a select group of severely ill patients who have APAP-

induced fulminant hepatic failure. Three and five-year survival rates post-transplant are 50% and 66%

due to advances in transplantation and supportive care. Survival rates among those with supportive

care alone, and who do not receive transplant is 25-40%.

• Referral to transplant unit criteria – King’s College Criteria

o CNS impairment (Encephalopathy, Altered mental state without sedative co-ingestion)

o Coagulopathy (INR >3 at 48hr or >4.5 at any time following ingestion, Severe

thrombocytopaenia, i.e., Plt <50)

o Metabolic (persistent acidosis pH <7.3 or blood lactate >3, Hypoglycaemia)

o CVS impairment (SBP <80 despite resuscitation)

o Renal impairment (Oliguria or Creatinine >200)

o KCC has a specificity of 90% and sensitivity 60%.

o There are limitations to the King’s College Criteria (Buckley & King, 2008).

• PT and INR are used to guide prognosis. The use of VitK, if effective, implies that transplant

unnecessary because viable liver remains, and vice versa. Clotting factor administration alters

interpretation and should not be used unless severe bleeding is present.

• Other criteria to determine need for transplantation exist, i.e., lactate clearance following APAP

ingestion, which can be added to KCC i.e., modified KCC. Lactate >4.7mmol/l at 55hr or after fluid

resuscitation, sensitivity 98%, specificity 58%, NPV 95%.

• Unfortunately, those who meet KCC and lactate criteria do so late in the course, which is not useful

in ED. Factors which are useful

include unintentional overdose/RSTI,

delays to NAC, doubling of ALT.

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Rumack-Matthew Nomogram

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Management of Immediate Release Paracetamol Poisoning Flowchart

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Management of Modified Release Paracetamol Poisoning Flowchart

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Management of Repeated Supratherapeutic Ingestions Flowchart

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Learning Objectives

By the end of the week, students should be able to:

• Describe the mechanism of toxicity and clinical effects of paracetamol poisoning (1.1.2; 2.1.1)

• Describe factors that influence risk assessment in paracetamol poisoning, including limitations of the

nomogram (6.1.1)

• Explain hepatic drug metabolism, including CYP450 enzymes, and factors that change activity

including drug interactions (1.1.1; 1.1.4).

• Explain the effect of drug formulation on toxicokinetics (1.1.1).

• Describe the acute management of paracetamol overdose, including decontamination and

monitoring (4.2.1; 4.3.1; 6.1.1; 6.1.4)

• Explain the scientific basis and use of acetylcysteine for the management of paracetamol poisoning

(4.3.2)

References

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the management of paracetamol poisoning in Australia and New Zealand. MJA 2020; 212(4):175-183

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Acetylcysteine.’ Elselvier – Sydney, Australia.

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