Transcript Paracetamol Poisoning

Paracetamol Poisoning
Kent R. Olson, M.D.
Clinical Professor of Medicine
University of California, San Francisco
Medical Director, San Francisco Division
California Poison Control System
Case Study:
A
17 year old young man took “pills” and some
alcohol after failing his exams. He is drunk and
depressed.
 BP
120/80
 Resp
 His
14/min
HR 105
Temp 37 C
airway is patent, he is breathing normally
Case, continued:
 He
is treated with intravenous fluids, watched
until sober, given a psychiatric referral, and
sent home with his family.
3
days later he returns with jaundice.
WHAT IS YOUR DIAGNOSIS?
Paracetamol poisoning
 Diagnosis
easily missed
– often overlooked in history
– no characteristic early symptoms or signs
Paracetamol Poisoning
 Common
analgesic
– often found in combination products
– eg, with antihistamines, codeine
Acetaminophen
Metabolism
~ 50%
~ 45%
P450
Glucuronidation
(non toxic)
~ 5%
NAPQI
Glutathione + NAPQI
= nontoxic product
Sulfation
(non toxic)
N-acetylcysteine (NAC)
Liver cell damage
Paracetamol Toxicity:
 Overdose:
– sulfation and glucuronidation saturated
– increased production of p-450 metabolite
• glutathione eventually depleted
• reactive intermediate NAPQI injures cells
PCM toxicity, cont.
 High-risk
groups: enhanced p-450 activity
– chronic alcoholics
– chronic use of isoniazid (INH)
Pharmacokinetics
 Tablets
dissolve rapidly
 Peak level 3-4 hours after ingestion
– May be delayed in the presence of other drugs
(eg, antihistamines, anticholinergics, opiates)
Pharmacokinetics, cont.
 Volume
of Distribution approx. 1L/kg
– Ingestion of 200 mg/kg ~ 200 mg/L est. blood level
 Elimination
half-life normally 1-3 hours
– Increased to 4-6 hours or more after overdose
Clinical Manifestations of Toxicity:
 Early:
non-specific
– anorexia, vomiting
Clinical toxicicity, cont.
 24-48
hrs:
– onset of liver injury
• AST, ALT may exceed 10,000 IU
– renal injury may also occur
Paracetamol Toxicity, continued:
 2-5
days:
– liver & kidney injury resolve in most patients
– some patients may develop fulminant liver failure
• progressive rise in PT/INR, bilirubin
• metabolic acidosis, hypoglycemia
• encephalopathy
• DEATH
Rarely - massive ingestions only:
>
600 mg/kg: early onset metabolic acidosis
– Not due to liver failure
– Probably mitochondrial poisoning
 One
case of massive ingestion >1500 mg/kg
– Coma
– Hypotension
– Acidosis
Prediction of Paracetamol Toxicity:
 History:
– acute ingestion of >200 mg/kg or >10 gm
• 20 tablets in average-sized person
– chronic use of >4-6 gm/day in a high-risk group
• Chronic alcohol abuse, isoniazid use
Prediction of PCM toxicity, cont.
 Clinical
evaluation:
– serum PCM level is best predictor, if available
– levels associated with “probable toxicity”:
• 200 mg/L at 4 hrs after acute ingestion
• 100 at 8 hrs
• 50 at 12 hrs
Tylenol “Extended Relief” Case:
1000
Serum PCM level
100
APAP
(mg/L)
10
Prob. Toxic
Poss. Toxic
1
0
5
10
15
20
Note: co-ingestion of Nyquil plus up to 44 g Tylenol ER
Ref: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510
25 hrs
Potential Pitfalls with Nomogram:
 Chronic
 Delayed
intoxication
or erratic absorption
– massive ingestion
– mixed ingestion with opioids, anticholinergics
 Very
early and transient increase in the PT/INR
may predict later LFT rise
– Normal PT/INR at 24 hrs may have good negative
predictive value
Gut decontamination for PCM
 NO
forced emesis
 Activated charcoal preferred
 Gastric lavage?
– only for massive ingestions (eg, > 600 mg/kg)
Treatment, continued
 Antidote:
N-acetylcysteine (NAC)
– provides SH group - binds to NAPQI
• most effective if started within 8-10 hrs after ingestion
– can be given PO or IV
– if vomiting, use IV route or give antiemetic
 Alternate
medication: oral methionine
Summary
 Ingestion
< 200 mg/kg probably not toxic
 If no serum level available treat based on dose
 IV acetylcysteine or oral methionine
 Start antidote within 8 hours
 Liver or kidney damage delayed 24-48 hrs