5 Paracetamol Flashcards
maximum total daily dose of oral paracetamol
500-mg paracetamol:
3000 mg/day
325-mg paracetamol:
3900 mg
children:
max of 75 mg/kg/day
[or five doses of 10-15 mkdose in a 24-hour period)
peak serum concentrations of oral paracetamol, when?
therapeutic doses:
30 mins to 2 hours
overdose:
within 2 hours
recommended dosing of IV paracetamol
> 50 kg:
650 mg every 4 hours, or
1000 mg every 6 hours
max total daily dose of 4 grams
<50 kg:
12.5 mg/kg every 4 hours, or
15mg/kg every 6 hours
max individual dose of 750 mg
max total daily dose of 75 mg/kg, or 3750 mg, whichever is less
peak concentration of IV paracetamol
occur at the end of the 15-min infusion period
pathophysiology of acetaminophen toxicity
- normally, acetaminophen is oxidized by the CYP450 system to NAPQI (N-Acetyl-P-benzoQuinone Imine), which is then detoxified by hepatic glutathione to a nontoxic compound that can be renally eliminated (APAP mercaptate?)
- however, when glutathione decrease to <30% of normal in the setting of overdose, NAPQI binds to hepatic macromolecules, resulting in CENTRILOBULAR HEPATIC NECROSIS
- hepatocyte damage progresses with cell lysis on the SECOND DAY, releasing transaminases and NAPQI-hepatic protein adducts in to the circulation where they are detected in the serum
-this corresponds generally to the development of OVERT CLINICAL TOXICITY
Stage 1 of acetaminophen toxicity
first 24 hours
may be asymptomatic or have nonspicific symptoms, such as anorexia, N/V, malaise
Stage 2 of acetaminophen toxicity
days 2-3
findings often improve
but clinical signs of hepatotoxicity - RUQ pain and tenderness- may occur
serum transaminases may be elevated
even without treatment, most patients with mild to moderate hepatotoxicity recover without sequelae
Stage 3 of acetaminophen toxicity
days 3 to 4
some patients will progress to fulminant hepatic feilure
Abdominal symptoms
Encephalopathy
Coagulopathy
Renal failure
Metabolic acidosis
stage 4 of acetaminophen toxicity
patients who survive the complications of fulminant hepatic failure begin to recover over the next 2 weeks (stage 4)
with complete resolution of hepatic dysfunction after 1-3 months
this may cause early-onset metabolic acidosis
ingestion of acetaminophen >500 mg/kg, or peak plasma conc’n >750 mcg/mL (or >5000 mmol/L)
with elevated lactate and altered sensorium
likely mechanism include
-depletion of liver glutathione stores
-resulting in generation of 5-oxoproline
-and metabolit-induced inhibition of mitochondrial respiration
toxic exposure of acetaminophen
1) >10 g or 200 mg/kg as a single ingestion or over a 24 hour period
2) >6 g or 150mg/kg per 24 hour period over at least 2 consecutive days
children <6 y/o
1) ≥200 mg/kg as a single ingestion or over an 8 hour period
2) 150 mg/kg per 24 hour period for the preceding 48 hours
graph for acetaminophen toxicity
Rumack-Matthew nomogram
toxicity line:
150 mcg/mL
1000 mmol/L
window: bet 4 and 24 hours after ingestion
previously:
>200 mcg/mL
>1300 mmol/L
-60% risk of developing hepatotoxicity (ALT >1000 IU/ML
-1% risk of renal failure
-5% risk of mortality
this has a 90% risk of developing hepatotoxicity
> 300 mcg/mL
2000 mmol/L
“toxicity line” for IV acetaminophen
any single IV acetaminophen dose abve 60 mg/kg
or acetamoinophen conc’n >50 mcg/mL at 4 hours
MOA of acetylcysteine
early acetaminophen poisoning (<8 hours after ingestino)
-acetylcysteine prevents the binding of NAPQI to hepatic macromolecules by acting as a glutathione precursor or substitute, or a sulfate precursor, or
-it may directly reduce NAPQI back to acetaminophen
in established acetaminophen toxicity, or >24 hours after ingestion
-it diminishes hepatic necrosis by acting as an to oxidant
»decreasing neutrophil infiltration
» improving microcirculatory blood flow, or
» increasing tissue O2 delivery and extration
remarks on acetylcysteine
If acetylcysteine is given within 8 hours of acetaminophen ingestion, it is nearly 100% effective in preventing the development of hepatotoxicity
adverse effect of acetylcysteine
anaphylactoid reactions in 4-17% or patients
most during the first 2 hours
mild cases are treated with diphenhydramine
severe cases are treated by temporarily slowing or stopping the infusion
regimen of IV acetylcysteine
21 hour protocol:
phase I:
loading dose of 150 mg/kg over 1 hour
phase II:
50 mg /kg over 4 hours
phase III:
100 mg/kg over 16 hours
IV acetylcysteine is commercially available as a 20% solution and requires dilution to a 2% solution for infusion into a peripheral vein
both 5% D5W and half-normal saline can be used as diluents
oral acetylcysteine regimen
72-hour oral acetylcysteine protocol:
140 mg/kg loading dose, then
maintenance doses of 70 mg/kg every 4 hours for 17 additional doses
The taste is disagreeable, may cause N/V, so u may give:
Ondansetron 4-8 mg IV/PO every 8 hours
a/e: QT prolongation
Indication of ECMO in paracetamol toxicity
“ExtraCorporeal Membrane Oxygenation”
in addition to acetylcystine
ONLY in the setting of encephalopathy,
metabolic acidosis,
elevated lactate, AND
acetaminophen level >900 mg/L
when can acetylcysteine be discontinued?
if the serum acetaminophen concentration is
<10 mcg/mL
<66 mmol/L
remarks on fulminant hepatic failure
most fatalities occur on days 3 to 5
those who survive generally begin to show evidence of recovery by days 5 to 7
survivors will eventually develop complete hepatic regeneration without any persistence of hepatic impairment
criteria for highest risk of mortality from acetaminophen-induced fulminant hepatic failure
King’s College Criteria
metabolic acidosis (arterial pH <7.30) despite fluid and hemodynamic resuscitation
or a cominabtion of
coagulopathy (PT >100s),
renal insuf (crea >3.3 mg/dL, >292 mcmol/L), and
grade III/IV hepatic enceph
treatment of fulminant hepatic failure
IV acetylcysteine therapy should be continued past the 21-hour standard regiment [at 6.25 mg/kg/hour] until
-the patient recovers,
-receives a liver transplant,
-or dies
massive acetaminophen overdose
> 40 grams or 500mg/kg
options:
-addition of oral acetylcysteine
-increasing the phase III to 200 mg/kg over 16 hours from 100 mg/kg over 16h
-or reloading the standard acetylcysteine regimen at completion of the 21-hour protocol
