Management of Acetaminophen Toxicity

1
Management of Acetaminophen Toxicity
2
History

• 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
Its everywhere!

• APAP is found in over 200 products
• Tylenol Anacin 3 Tempra
• Tylenol cold Goodys Comtrex multi sx
• Contac Severe Cold Junior Strength Tylenol Vicks
  Nyquil
• Sinutab Sinus Theraflu Sine-off
• Sinarest Robitussin Cold Panadol
• Midol PMS Sudafed Sinus Vanquish
• Vicks 44M Unisom Singlet
• Pyrroxate Midol teen Coricidin
• Dimetapp allergy Drixoral Cold Alka Seltzer
  Plus
• Actifed Sinus Benadryl allergy Panex

4
Actions

• Analgesia
• Relieves mild to moderate pain
• Efficacy equivalent to salicylates
• Inhibits brain prostaglandin synthetase
• Blocks pain impulses peripherally

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

10

• Excretion
• APAPs metabolic products are excreted by the
  kidneys
• Minimal excretion into breast milk

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

12

• Extracorporeal elimination
• Hemodialysis
• Not proven effective in reducing or preventing
  liver damage in overdose
• Peritoneal dialysis
• Not effective

13
Toxicity

• Factors involved in predicting hepatotoxicity
• 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 gt 150 mg/kg in acute dose
• Adults gt 7.5 Grams in 24 hours (chronic)
• Children (lt10 yrs) gt 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

22

• Hemodialysis
• Limited benefit
• Damage occurs quickly
• Hemoperfusion
• No benefit
• Peritoneal dialysis
• No benefit

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

• 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
150
500
Late
100
Not valid after 24 hours
50
10
5
mcg/ml 4 8 12
16 20 24
Hours After Acetaminophen Ingestion
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
4 or more hours since overdose
Less than 2 hours More than 2 hours
since overdose since
overdose
Gastric emptying Activated
charcoal Activated charcoal
Draw blood plasma 4 hours after overdose
for plasma acetaminophen assay
Draw blood ASAP for plasma acetaminophen
assay
Acetaminophen concentration available
Acetaminophen concentration not
within 8 hours of overdose
available within 8 hours of
overdose
Wait for acetaminophen assay result
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 LFTs, 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.

38
Signs/symptoms

• Patient is awake and alert
• HEENT normal
• No GI distress
• PERRLA
• Temp 98.7F
• HR 84, BP 128/76, R 19

39
Lab results

• APAP pending
• Salicylate pending
• Tox screen Negative

40
Calculations

• Patient weighs 60.9 kilograms
• 15,500 mg of APAP ingested
• mg/kg 254
• a potentially toxic acute dose

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
(No Transcript)
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

48
Signs/symptoms

• Patient has vomited x 6 prior to arrival
• Complaining of GI discomfort
• HEENT normal
• PEERLA
• Temp 98.9F
• HR 80, BP 130/78, R 20

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 gt 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

• APAP is present in many poly drug overdoses
• No symptoms may be presentscreen
• 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

54
The End