APAP (paracetamol)

Related FACEM curriculum (2022) learning objectives:

• ME 3.8.1.4(h) Principles of assessment of toxicological presentations in the ED, including: Common presentations (e.g. paracetamol, quetiapine, SSRI)

#completed #carded

History

• First synthesised in 1878
• Clinical use began in 1950-70s
• Multiple names in use
• Often packaged in combination products
• Many controversies still exist in toxicity
  • Combination products and new presentations

Pharmacodynamics

• Indirect inhibition of prostaglandin H2
  • Reduction of heme group on peroxidase part of PGH2
  • In contrast to NSAIDs with direct COX inhibition
• Relatively selective for brain tissue (low peroxide tone)
  • Stronger inhibition in areas of low “peroxide tone” (i.e., low peroxidase, arachidonic acid activity)
  • Thus seems to have lower activity in immune cell and platelets
• Thus functionally a centrally acting COX-2 selective inhibitor
• Therapeutic concentrations - analgesic (10 mg/L) and antipyretic (4 – 18 mg/L)
• Other proposed receptor activity:
  • Descending serotonergic pathway activation (human, rat) which is antagonised by serotonin antagonists
  • APAP opposed by opioid receptor antagonists (but APAP doesn’t bind these receptors – mechanism unknown)
  • Theorised APAP metabolite activating cannabinoid system – controversial
  • TPRV1 receptors activated by metabolite – seems to be analgesic (in mice)

Pharmacokinetics

Absorption

• Peak absorption 30 (liquid), 45 (IR tablet), 60 – 120 (MR) minutes
• Bioavailability – 60-98% (oral) 30-40% (rectal)

Distribution

• Vd - 1L/kg
• Peak therapeutic concentrations – 8 – 20 mg/L ("recommended doses" PO), 4 – 13 mg/L (20-25mg/kg PR), 30 mg/L (1g IV)
• Enters CSF within 15 minutes (IV) and 45 minutes (PO / PR)
• Protein binding – 10%-30% (even in overdose)
• Crosses into placenta/breast milk

Metabolism

• 90% undergoes hepatic conjugation – glucuronidation (40-67%) and sulfation (20-46%)
• 5% excreted unchanged
• 5% oxidised by CYP2E1 (and in smaller amounts by 3A4, 2A6 and 1A2)
  • Forms toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI)
  • Glutathione (GSH) rapidly conjugates into non-toxic substances

Elimination

• 5% excreted unchanged
• Glucuronide, sulfate and glutathione conjugates (cysteine and mercaptate) all excreted in urine
• Elimination half-life- 2-3 hrs (prolonged in acute liver injury)

Toxicokinetics

• Most absorption in 2 hours, complete by 4 hours
• Secondary peak levels seen in large ingestions (>50 g) or with antimuscarinics
• NAPQI production largely due to CYP2E1 in overdose
  • Basal proportion (5%) metabolised can become 20-50%
  • Saturation of sulfation conjugation pathway
  • Glucuronidation not saturable, but rates metabolised highly variable in overdose
• Estimated serum APAP levels (not fully described) after overdose
  • 15mg/kg - 10mg/mL
  • 75mg/kg - 35mg/L
  • 146mg/kg - 117mg/L

Pathophysiology

Hepatic injury

• Glutathione storage generally exceeds that required to detoxify NAPQI in therapeutic dosing
  • Depleted in overdose
• NAPQI binds to hepatocyte components causing hepatocellular necrosis
  • Initially and predominantly affects hepatic zone III
    • Can extend into zones I and II in severe toxicity
  • NAPQI binds to cysteine portion of intramitochondrial proteins, creating drug-protein adducts
  • Covalent binding and arylation (more predictive of toxicity) of proteins within cell
  • Induces cellular death via cascade of events
    • Mitogen-activated protein kinase activation
      • Opening of mitochondrial transition pores (MTP) -> increased permeability
      • Decreased mitochondrial respiration
      • Decreased ATP synthesis
    • Opening of MTP releases intramitochondrial proteins
      • Endonuclease G
      • Apoptosis inducing factor
    • These lead to DNA fragmentation and cellular necrosis
      • Apoptosis occurs early in APAP toxicity but is not the major mechanism of cell death
      • Heralded by release of damage-associated molecular patterns (DAMPs)
      • Specifically, DNA fragments, heat shock proteins, HMGB-1
      • Activation of toll-like receptors on Kupffer cells (liver macrophages)
      • Cytokine and nitric oxide release
      • Release of intracellular biomarkers – AST, ALT, microRNA 122, HMGB-1, keratin-18 and drug-protein adducts
      • Inflammatory cascade after necrosis induces further hepatocyte injury
• Additional mechanisms of toxicity include nitric oxide release and altered protein expression
• Secondary multi-organ effects as would be expected from hepatic failure generally

Renal effects

• Acute kidney injury likely due to ATN due to local NAPQI produced by renal CYP2E1
  • Also possibly by renal COX-2 and prostaglandins in chronic nephropathy
  • Possibly also due to conversion of APAP and glutathione conjugates into nephrotoxic metabolites
• Hepatorenal syndrome
• Volume depletion
• Potassium wasting
  • Renal vasoconstriction due to COX inhibition
  • Direct NAC effect

CNS effects

• Rarely reported
• Possibly due to serotonin/opiate receptor effect or CNS glutathione depletion

Metabolic effects

• Metabolic / lactic acidosis from altered mitochondrial respiration
• 5-oxoprolinaemia (pyroglutamic acidaemia) rarely seen
• Typically older women with chronic APAP use and chronic kidney disease
• Possibly genetic polymorphism of glutathione synthase and 5-oxoprolinase
• In combination with oxidative stress and inflammation
• Sources of 5-oxoproline (gamma-glutamyl cycle):
  • Increased substrate (gamma-glutamyl cysteine)
    • Produced from glutamic acid
    • Production increased with decreasing glutathione levels
    • Gamma-glutamyl cysteine synthase, is inhibited by glutathione via negative feedback loop
  • Decreased metabolism
    • 5-oxoprolinase converts 5-oxoproline/pyroglutamic acid to glutamic acid
    • Inhibited by flucloxacillin and vigabatrin
    • Possibly less active in women
  • Decreased clearance – renal failure

Clinical Presentation

• Early recognition and treatment is essential.
• Screening patients, particular with deliberate overdose of other agents, is reasonable
• Hepatotoxicity defined as a peak AST/ALT of over 1000IU/L.
  • Acute liver injury for lower levels.

Four stages of toxicity

• Stage I – initial stage
  • Hepatic injury is delayed – initial biomarkers will be negative unless delayed presentation
  • Elevated APAP levels often only feature
  • Asymptomatic, or mild non-specific GIT/constitutional symptoms
  • Severe mitochondrial dysfunction can cause metabolic derangements, depressed conscious state and death (even with normal LFTs)
• Stage II – onset of acute liver injury
  • <5% of patients
  • Within 12 – 36 hours, occurs earlier in this period in more severe poisonings
  • AST is the most sensitive test (precedes synthetic and clearance dysfunction)
  • AST rises and falls earlier than ALT, but ALT can also be used
  • APAP-cysteine adducts peak with AST
• Stage III – peak of liver injury
  • Between 72 – 96 hours after ingestion
  • Fulminant hepatic failure at this stage, if it occurs
  • ALT/AST levels highly variable, but can be >10,000IU/L
  • Functional markers (coagulation, glucose and lactate) and metabolic state more predictive of prognosis
  • Risk of associated acute kidney injury increased in this group (50-80% vs <1%)
  • Creatinine rise day 2 – 5 with peak at day 3 – 16.
  • Normalise without treatment after 1 month
  • Death, if it occurs, around this time
• Stage IV – recovery
  • Usually biomarkers are normalised by day 7
  • Except creatinine (1 month) and sometimes ALT is occasionally downtrending
  • Histological abnormalities may last for months

Resuscitation

• Attend to ABCDs as usual. No specific resuscitation measures.

Risk Assessment

• Probably the most challenging aspect of managing the APAP poisoned patient
• 'At risk' exposures from 7.5g (paeds: 150mg/kg) to 12g (200-350mg/kg)
  • More likely on the upper end of this range
  • 10g / 200mg/kg used in Australia as threshold
• Consider reliability of history particularly in deliberate self-harm
• Interpretation of [APAP] made with the Rumack-Matthew nomogram
  • A linear plot of log-concentration of APAP vs time
  • Based on historical data on patients who developed hepatotoxicity (rather than hepatic failure)
  • Used to guide treatment with N-acetylcysteine
  • Drawn from APAP concentration of 1300 mcmol/L (200mg/L) at 4 hours
  • Arbitrary safety margins added to the nomogram
    • In Aus / US, reduced by 25% (1000mcmol/L or 150mg/L)
    • In the UK, low risk patients are treated under original line 200mg/L and high risk patients under 100mg/L
  • Risk of developing hepatotoxicity (<1%) below line exceedingly rare, and hepatic failure (<0.05%) even more so

Situations where the nomogram is not applicable

Uncertain time of ingestion

• Treat based on worst-case time if given a range
• If no time range at all with detectable [APAP] or elevated [AST/ALT], assume delayed (>24 hours) and treat with NAC.

Modified release APAP

• May demonstrate 'nomogram crossing' after initial 4 hour level
• Variation in practice internationally
  • US use their immediate-release APAP
  • Aus/NZ start treatment based on dose (>10g / 200mg/kg) and continue if serial 4 hourly levels cross the nomogram

Intravenous APAP

• Hepatoxicity reported with single exposures of 75-150mg/kg and repeated exposures of 59-77mg/kg/day
• Generally in children as decimal-point errors, confusion between mg and mL and incorrect route
• Limited information regarding risk threshold of exposure
  • Reasonable to start treating single exposures if >60mg/kg in until [APAP] undetectable
  • Reasonable to treat repeated exposures if there is evidence of liver injury or evidence of [APAP] accumulation (based on expected concentration relative to last dose)

Repeated (supratherapeutic) ingestions

• Unclear threshold for risk
  • Prospective data suggesting doses of 6-8g/day is not associated with liver injury
  • However, case reports of the same in those with slightly supratherapeutic repeat ingestions
  • Probably due to patient factors (GSH stores, 2E1 activity, NAPQI formation)
• History can especially be unreliable in these cases
• Australian guidelines - investigate and treat patients:
  • With signs and symptoms (abdominal pain, nausea, vomiting) in those who've taken therapeutic dosing (> 4g or 60mg/kg in 24 hours) over a 48 hour period
  • Or based on exposure alone:
    • 10g or 200mg/kg in 24 hours
    • 12g or 300mg/kg in 48 hours

Considerations in pregnancy

• No alteration in treatment necessary
• Risk of not treating mother regarding harm in case of maternal hepatotoxicity to fetus higher than treating with NAC
• APAP crosses the placenta
  • Foetal metabolism poorly understood but probably inefficient
  • Sulfation likely the predominant mechanism
  • Glucuronidation does not seem to occur until after 23/40 gestation
  • CYP450 oxidation highly inefficient (10% at 18/40 gestation, 20% at 23/40).
  • Unclear how decreased conjugation but also decreased NAPQI production affects foetus
• Limited data on adverse effects of NAC on the foetus (but experience suggests it is safe)

Ethanol and APAP

• Acute ethanol ingestion is protective of hepatocytes
  • Probably through competitive inhibition of CYP2E1
• Chronic ethanol use increases the risk however
  • Induction of CYP2E1
  • Decreased mitochondrial glutathione stores
  • However, likely a negligible increase of risk with respect to the treatment nomogram line as used currently (as they were included in the original dataset)

CYP2E1 inducers

• Isoniazid is a potent CYP2E1 inducer that is thought to increase NAPQI production
• Other relevant drugs include phenytoin, carbamazepine and phenobarbital (non specfic induction of CYP enzymes)
• Other CYP2E1 inducers commonly seem include colchicine, nicotine and rifampin

Predictors of mortality and morbidity

King's College Criteria (KCC)

• Developed and validated in patients with APAP-induced fulminant hepatic failure
• Sensitivity 47% and specificity 83% for death or transplant
• Survival was 25-40% in this cohort in original studies
  • This may be different now due to increased use of NAC)
• Criteria:
  • pH < 7.3 or [Lactate] > 3.0mmol/L after fluid resuscitation; OR
  • All of:
    • [Creatinine] > 300mmol/L
    • INR > 6.5
      • Need to be mindful that NAC and exogenous clotting factors, if given, can distort INR
    • Grade III or IV encephalopathy

Other early predictors

• Most have been found to be less sensitive than KCC:
  • MELD > 32
  • Serum Gc-globulin
  • Factor V and Factor VIII:V ratio
  • Day 4 PT and INR
  • PT > hours since ingestion
• APACHE II > 15 is as specific as KCC
• APACHE II score > 60 is an independent predictor for need for liver transplant
• The combination of KCC, APACHE II > 11, SOFA > 12 is most specific for those who need transplant
  • MELD > 32 and lactate >4.7mmol are more sensitive
• Other scores (not in general clinical use)
  • [APAP] x [higher of AST/ALT] > 1500
    • Sensitive but not very specific in predicting coagulopathy
  • APAP Psi parameter/nomogram
    • Uses [APAP] and time to NAC treatment
    • Very sensitive (97%) and specific (92%) in predicting hepatotoxicity, but less so with coagulopathy

Risk factors on history

• Unintentional overdose
• Repeated (supratherapeutic) dosing
• Delays to NAC treatment

Supportive care

• Renal and hepatic support based on general principles.
• Monitor and treat hypoglycaemia
• Coagulopathy
  • Haemorrhage is rare, but FFP / clotting factors / prothrombin complex concentrate can be considered if bleeding or high-risk intervention
  • Variance in Vitamin K use
    • No benefit if no meaningful hepatocyte function
    • But some authors suggest a trial dose is not unreasonable (if there are limited viable hepatocytes)
• Manage of hepatic encephalopathy and prevention of cerebral oedema

Investigations

• Evolving frequently in light of new evidence, techniques and changes in paracetamol formulations
• Ideal biomarkers would involve individual CYP2E1 function, glucuronyl- and sulfo- transferase activity, NAPQI and glutathione (GSH) levels. However, these are not available.
  • Protein adducts are being studied
    • Provides evidence of intrahepatic protein binding to APAP
    • However, this is only one of two conditions for toxicity, the other being an inflammatory response
    • Cysteine-APAP adduct level representing toxicity uncertain
  • Serum GSH levels have an uncertain relationship to hepatic GSH levels
  • miRNA-122 – liver specific micro RNA released during cell lysis
    • Correlates with INR and peak ALT
    • Increases earlier than ALT/AST so may have a role in earlier determination of risk
  • Keratin-18 (nK18) - epithelial/hepatic cell filament protein
    • Also increases earlier than ALT in hepatotoxicity
  • High-Mobility Group Box-1 (HMGB-1)
    • Passively released during necrosis of hepatocytes
    • Targets toll-like receptors and initiates inflammatory cascade
    • Elevated in APAP-associated hepatotoxicty, correlates well with peak INR and LFT, and rises earlier
    • Acetylated form seems to be present only in patients who later die or meet King's College criteria
    • Therefore is a promising marker of potential severity
• During phase I, the only useful test is APAP concentration
  • An undetectable [APAP] at 2-4 hours effectively excludes APAP exposure
  • Levels taken before 2 hours should be ignored (reports of clinically relevant levels at 4 hours when these levels were not detected initially exist)
  • See Risk Assessment for details for interpretation
• INR / PT derangements can be seen in the absence of liver injury
  • Due to direct effect of APAP:
    • Seen at 4-24 hours after ingestion
    • Due to NAPQI-related inhibition of gamma-carboxylation of Vitamin K-dependent clotting factors
  • Due to NAC:
    • Interferes with the assay
    • Reversal of NAPQI inhibition
    • Direct effect
• Renal impairment due to APAP toxicity is not seen without significant hepatotoxicity

Decontamination

• Activated charcoal
  • APAP has rapid absorption
  • Clear benefit if given within 2 hours
    • Benefit beyond this less clear
  • Previous controversy regarding its use when PO NAC regimens – this has been discounted
• Gastric lavage not recommended

Enhanced Elimination

• Intermittent haemodialysis
  • May be useful in very high [APAP]
  • Recommended when:
    • [APAP] > 700mg/L (>900mg/L with NAC) and metabolic/lactate acidosis or altered mental state
    • [APAP] > 1000mg/L irrespective
  • Extraction ratio 50-80% in overdose
  • Also removes NAC in with a similar extraction ratio
    • Reasonable to therefore double NAC dose on IHD
  • Extraction ratio of NAC with CVVHDF is 13% (therefore no dose adjustment required)
  • Also useful for treatment of metabolic consequents of fulminant hepatic failure and hepatorenal syndrome
• Plasma exchange
  • Removes only small amounts of APAP in therapeutic dosing
  • Perhaps useful only for correcting coagulopathy
• Liver dialysis
  • Molecular adsorbent recirculation system
    • Improves encephalopathy and cerebral blood flow
    • Improves haemodynamics
    • No improvement in mortality (not specific to APAP however)
    • Possibly very effective in removing APAP from circulation
  • Other modalities not well studied

Antidotes

• N-acetylcysteine (NAC)
• Those commenced on NAC empirically can have treatment stopped and be discharged:
  • If [ALT] < 50IU/L and [APAP] below treatment line (6-24 hours) or < 66mcmol/L (>24 hours since exposure)
  • Otherwise should continue NAC treatment
• Those who complete a 20 hour NAC course can be discharged if [ALT] is <50IU/L or falling and [APAP] <66mcmol/L, otherwise should proceed onto extended NAC
  • Extended NAC
    • Further serial doses of 100mg/kg of NAC over 16 hours
    • Requires BD monitoring of [ALT], INR +/- [APAP]
    • Stop NAC and discharge when:
      • [ALT] decreasing
      • [APAP] < 66mcmol/L
      • INR < 2.0
      • Patient remains well

Disposition

• Discuss all patients who meet King's College Criteria with a liver unit
• All deliberate self-poisonings need psychiatric assessment
• After NAC treatment if required as described above

References

1. Nelson LS, Goldfrank LR. Goldfrank’s toxicologic emergencies. 11th ed. New York Mcgraw-Hill Education; 2019.
2. Cytochrome P-450 CYP2E1 Inducers | DrugBank Online
3. https://derangedphysiology.com/main/cicm-primary-exam/required-reading/acid-base-physiology/acid-base-disturbances/Chapter 618/pyroglutamic-acidosis
4. Paracetamol poisoning. eTherapuetic Guidelines.