2. History
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Synthesized in 1877 in U.S.
Extensive use began around 1947
Initially prescription only in the U.S.
Otc status gained in 1960
toxic effects first noted in U.S. in 1971
3. It’s everywhere!
• APAP is found in over 200 products
Tylenol
Tylenol cold
Contac Severe Cold
Sinutab Sinus
Sinarest
Midol PMS
Vicks 44M
Pyrroxate
Dimetapp allergy
Actifed Sinus
Anacin 3
Goody’s
Junior Strength Tylenol
Theraflu
Robitussin Cold
Sudafed Sinus
Unisom
Midol teen
Drixoral Cold
Benadryl allergy
Tempra
Comtrex multi sx
Vicks Nyquil
Sine-off
Panadol
Vanquish
Singlet
Coricidin
Alka Seltzer Plus
Panex
5. • Antipyresis
• Efficacy similar to salicylates
• Inhibits prostaglandin synthetase in the
hypothalamus
6. In overdose situations, liver enzymes become
saturated, glutathione is depleted, NAPQI
(N-acetyl-p-benzoquinoneimine)
accumulates, and hepatic necrosis occurs
7. Pharmacokinetics
• Absorption
– Rapidly absorbed from the GI tract
– Peak concentration usually occurs between 60
and 120 minutes
– Peak plasma levels almost always occur within
4 hours
8. Distribution
• Vd 1.0 - 2.0 L/Kg
• Approximately 20% plasma protein bound
may increase to 50% in overdose
• Has been reported to cross the placenta
9. Metabolism
– Occurs via several pathways in the liver
• 52% by sulfation
• 42% by glucuronidation
• 2% excreted unchanged in the urine
• 4% biotransformed by C-P450 MFO system
11. Half life
• Average 2 hours
– range 0.9 to 3.25 hours
• No age related differences
• No change in patients with renal disease
• With liver dysfunction, may increase to 17
hours
13. Toxicity
• Factors involved in predicting hepatotoxicity
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total quantity ingested
time from ingestion to treatment
age of the patient
alcoholism
enzyme inducing medications
♣ serum concentration in relation to Rumack
nomogram
14. • Toxic dose
– In adults, threshold for liver damage is 150 to
250 mg/kg
– Children under 10 appear to be more resistant
15. • Potential liver damage
– Adults: > 150 mg/kg in acute dose
– Adults: > 7.5 Grams in 24 hours (chronic)
– Children (<10 yrs): > 200 mg/kg
16. 4 Stages of Acetaminophen
Poisoning
• Phase I (30 minutes to 4 hours)
– Within a few hours after ingestion, patients
experience anorexia, nausea, pallor, vomiting,
and diaphoresis. Malaise may be present.
Patient may appear normal
17. • Phase II (24 to 48 hours)
– Symptoms of Phase I are less severe. May seem
like a period of recovery. Right upper quadrant
pain may be present due to hepatic damage.
Blood chemistry becomes abnormal with
elevations of liver enzymes. Prothrombin times
may be prolonged. Renal function may begin
to deteriorate.
18. • Phase III (3 to 5 days)
– Characterized by symptoms of hepatic necrosis.
Coagulation defects, jaundice, and renal failure
have all been noted. Hepatic encephalopathy
has been noted. Hepatic biopsy at this time
would indicate centrilobular necrosis. Nausea
and vomiting may reappear. Death is due to
hepatic failure
19. • Phase IV (4 days to 2 weeks)
– Complete resolution or death
20. Treatment
• GI decontamination
– Syrup of Ipecac
• return usually 30-40% at best
• best if used early (first 1-2 hours)
– Gastric lavage
• effectiveness diminishes with time
21. • Activated charcoal
– Should not be witheld
– dose 50-100 Grams
• Cathartic
– utilized to speed transit time
23. Blood Sample
• 4 hour post ingestion APAP level
– levels drawn earlier may be
erroneous
– levels may be accurate out to 18
hours
24. • Plot level on Rumack-Matthews
nomogram
– 150 mg/dl at 4 hours is possibly toxic
– Do not use therapeutic “normal” values to
determine potential toxicity!
25. •
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Baseline CBC
creatinine, BUN, blood sugar, electrolytes
prothrombin times
AST, ALT
– repeat q 24 hours
– elevations typically seen 24-36 hours post
ingestion
26. Rumack and Matthew Nomogram
500
Late
150
100
50
Not valid after
24 hours
10
5
mcg/ml
4
8
12
16
20
Hours After Acetaminophen Ingestion
24
27. • If APAP level plots above the possible risk
line administer N-acetylcysteine (NAC).
• If NAC is indicated, full regimen should be
followed. Do not stop NAC early if
nomogram indicates toxic possibility
28. N-acetylcysteine (NAC)
• Mechanism of action
– glutathione substitute
– may supply inorganic sulfur, altering
metabolism
• Route of administration
– Orally or IV
• IV not approved in the U.S.
29. • NAC dosing
– Oral 72 hour protocol
• Loading dose is 140 mg/kg
• Maintenance doses: 70 mg/kg
– Given every 4 hours x 17 doses starting 4 hours after
loading dose
30. • NAC supplied as 10 or 20% oral solution
– dilute to 5% final concentration with juice or
soft drink
– May be administered via NG tube
– If emesis occurs within 1 hour of
administration, repeat the dose
31. • If emesis persists, antiemetics may be used
– Reglan® (metoclopramide)
• 0.1 to 1.0 mg/kg iv is often effective
– If emesis is refractory, may consider
Zofran® (ondansetron) or Kytril® (granisetron)
• Expensive, but very effective
32. Pediatric overdoses
• More resistant to toxicity vs. adults
– if a child plots in the possible risk category on
the Rumack nomogram, do not resist using
NAC because of this greater tolerance to APAP
– Administer full course of NAC if nomogram
indicates that it is needed
33. Special considerations with NAC
• NAC administered on basis of nomogram
plot
• if initial level indicates need for NAC do
not discontinue
• subsequent APAP levels of interest only
• If NAC begun before APAP level obtained,
may DC NAC if level plots subtoxic on
nomogram
34. NAC side effects
• Relatively free of side effects when given
orally
• Emesis may occur
– extremely offensive sulfur odor
35. ED Admission
Estimate time of ingestion
Less than 4 hours since overdose
Less than 2 hours
since overdose
More than 2 hours
since overdose
Gastric emptying
4 or more hours since overdose
Activated charcoal
Activated charcoal
Draw blood plasma 4 hours after overdose for
plasma acetaminophen assay
Acetaminophen concentration available
within 8 hours of overdose
Wait for acetaminophen assay result
Draw blood ASAP for plasma
acetaminophen assay
Acetaminophen concentration not
available within 8 hours of overdose
Start NAC pending assay result
Loading does: 140 mg/kg
APAP level below risk line on nomogram
APAP level on or above risk line
DC NAC if started
Treat with full course of NAC
No further medical management needed
Daily LFT’s, prothrombin times
Treat other med or psychiatric problems
Provide supportive care
36. Summary
In overdose, APAP may overwhelm the liver
stores of glutathione. A rise in liver enzymes may
occur, which reflects the hepatic toxicity which
may ensue. Timely administration of NAC may
protect the patient from hepatic damage. Therapy
should be initiated as soon as possible, but NAC is
beneficial at any time. If APAP levels can not be
obtained, assume a toxic dose has been ingested,
initiate NAC, and continue until regimen
complete.
37. Case Studies
Case 1
A 32 year old female presents to the ED 30
minutes after taking 31 Tylenol Extra
Strength caplets in an apparent suicide
attempt. She weighs 134 pounds,
ambulated into the ED, is in no obvious
distress, has had no symptoms prior to
arrival.
41. Treatment
• Lavage
• Activated charcoal
• Cathartic
– Hold NAC until APAP level results obtained
• can get APAP level back within 2 hours
42. Outcome
• APAP level 56 mg/dl drawn 4 hours post
ingestion
• ASA level 0
• patient discharged asx to mental health unit
7 hours after arrival
43. Case 2
A 25 year old male is brought to the ED by
his girlfriend. She states that he has taken
24 “Tylenol” tablets. She brought the bottle
with her and in fact the product is “Tylenol
ER”. He ingested the caplets approximately
5 hours ago.
44. Tylenol ER is a relatively new product
which throws a curve into the traditional
management of APAP overdoses. This
product releases 325 mg of APAP
immediately and 325 mg over the next 8
hours.
45.
46. Tylenol “ER” is referred to by poison center
staff as
Tylenol Emergency Room
47. • Unsure if nomogram is useful with this
product
• 1 case demonstrated to have biphasic peaks
49. Labs
• APAP level 110 mcg/ml at 5.0 hours post
ingestion
• ASA level 0
• Tox screen negative for other substances
50. Calculations
• Patient weighs 85 kilograms
• 11,050 mg APAP was ingested
• 183 mg/kg APAP ingested
– Potentially toxic amount in acute od
51. Treatment
• Activated charcoal with sorbitol given
• Repeat APAP level 4 hours past the 1st
level
• Strongly consider NAC with this level
– Initial 4 hour level > 100 start NAC
52. Outcome
• Patient was treated with full course NAC
• Liver enzymes were AST 220 U/L, and
ALT 388 U/L at 27 hours post ingestion.
• Liver enzymes returned to normal ranges
within 72 hours.
• Patient recovered uneventfully
53. Points to remember
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APAP is present in many poly drug overdoses
No symptoms may be present…screen
150 mcg/ml at 4 hours is a “treat” level
NAC loading dose is 140 mg/kg
NAC maintenance doses are 70 mg/kg
Once NAC is started, DO NOT DC
Metoclopramide 0.1-1.0 mg/kg is very effective in
controlling nausea/vomiting associated with
APAP toxicity
APAP (N-acetyl-p-aminophenol_
Paracetamol in the UK, Mexico, many other countries
Now surpasses ASA as a major cause of poisoning in US
Use incr. Dramatically as Reyes syndrome was linked to salicylate use.
Now considered “safed” than aspirin
One of the most commonly used analgesic/antipyretic agents in the US
Has none of ASA’sunderirable side effects when used in therapeutic dose
Due to this increased availability and use, toxic exposures have also increased.
Toxic effects seen in great Britain in late 1960’s.
In each of the last few years, over 60,ooo queries related to APAP thru TESS each year
In over 50 “Trade” name products
Some are APAP alone, many others in combo with other agents.
Most pain meds today contain APAP
Codeine/APAP, Hcodone/APAP,
Oxycodone/APAP
Suppositories, elixirs, tablets, caplets, geltabs, capsules, powdered (Tylenol Cold?Flu)
some up to 1000 mg/dose
Peripheral action is blockade of Pain Impulse generation
Less effect on peripheral enzyme
Studies have shown that both apap and asa have equal effects on pain when given in equiv. Doses when the pain in non inflammatory in origin
For inflammatory pain, salicylates are superior.
They also inhibit prostaglandin synthetase peripherally, resulting in anti inflammatory activity.
Inhib. Prost. Snythetase in the hypothalamus, altering response of the heat regulating center.
Studies comparing APAP and ASA have shown no significant difference in temperature response, time of onset, time of peak activity, or duration of antipyretic activity
Peak concentration occur even more quickly with liquid formulations
Bezoar formation has not been seen with APAP like it has with ASA
The 4% metab by the P450 system is an active intermediate (NAPQI)
Normally, this minor metabolite of hydroxylation is detoxified by conjugation with hepatic glutathione, with the conjugated products mercapturic acid and cysteine excreted in the urine
When large doses of APAP are ingested, both the glucoronidation and sulfation pathways become saturated, shunting more APAP toward the P-450 system and increasing NAPQI formation.
When glutathione depletes to 30% of normal, NAPQI accumulates. The NAPQI arylates to protein in the cytosol and endoplasmic reticulum in the centrilobular zone of the liver, producing cell necrosis and death.
NAPQI is neutralized by glutathione
NAPQI contains a sulfhydryl group. If all glutathione is used up, other sulfhydryl groups in the liver are attacked and cells are damaged or destroyed
Haemodialysis readily removes APAP, but the toxic metabolite is formed rapidly
Peritoneal dialysis- Protein binding may increase up to 50% in overdose
Forced diuresis- Not effective because of small amount excreted unchanged in the urine.