Management of Acetaminophen

Toxicity

HistoryHistory

• 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 1971toxic effects first noted in U.S. in 1971

It’s everywhere!

• APAP is found in over 200 products

Tylenol Anacin 3 Tempra

Tylenol cold Goody’s 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

Actions

Analgesia

Relieves mild to moderate painEfficacy equivalent to salicylates Inhibits brain prostaglandin synthetaseBlocks pain impulses peripherally

• Antipyresis• Efficacy similar to salicylates

• Inhibits prostaglandin synthetase in the

hypothalamus

In overdose situations, liver enzymes become saturated, glutathione is depleted, NAPQI

(N-acetyl-p-benzoquinoneimine) accumulates, and hepatic necrosis occurs

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

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

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

Excretion

• APAP’s metabolic products are excreted by the kidneys

• Minimal excretion into breast milk

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

Extracorporeal elimination

• Hemodialysis– Not proven effective in reducing or

preventing liver damage in overdose

• Peritoneal dialysis– Not effective

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

• Toxic dose

– In adults, threshold for liver damage is 150 to 250 mg/kg

– Children under 10 appear to be more resistant

• Potential liver damage

– Adults: > 150 mg/kg in acute dose

– Adults: > 7.5 Grams in 24 hours (chronic)

– Children (<10 yrs): > 200 mg/kg

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

• 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.

• 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

• Phase IV (4 days to 2 weeks)

– Complete resolution or death

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

• Activated charcoal– Should not be witheld– dose 50-100 Grams

• Cathartic– utilized to speed transit time

• Hemodialysis– Limited benefit– Damage occurs quickly

• Hemoperfusion– No benefit

• Peritoneal dialysis– No benefit

Blood Sample

•4 hour post ingestion APAP level– levels drawn earlier may be

erroneous

– levels may be accurate out to 18 hours

• 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!

• Baseline CBC

• creatinine, BUN, blood sugar, electrolytes

• prothrombin times

• AST, ALT– repeat q 24 hours– elevations typically seen 24-36 hours post

ingestion

mcg/ml 4 8 12 16 20 24

Hours After Acetaminophen Ingestion

150

5

10

50

500

Rumack and Matthew Nomogram

100

Late

Not valid after 24 hours

• 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

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.

• 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

• 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

• 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

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

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

NAC side effects

• Relatively free of side effects when given orally

• Emesis may occur– extremely offensive sulfur odor

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 LFT’s, prothrombin times

Treat other med or psychiatric problems Provide supportive care

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.

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.

Signs/symptoms

• Patient is awake and alert

• HEENT: normal

• No GI distress

• PERRLA

• Temp 98.7°F

• HR 84, BP 128/76, R 19

Lab results

• APAP pending

• Salicylate pending

• Tox screen Negative

Calculations

• Patient weighs 60.9 kilograms

• 15,500 mg of APAP ingested

• mg/kg = 254– a potentially toxic “acute” dose

Treatment

• Lavage

• Activated charcoal

• Cathartic– Hold NAC until APAP level results obtained

• can get APAP level back within 2 hours

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

Case 2A 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.

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.

Tylenol “ER” is referred to by poison center staff as

Tylenol Emergency Room

• Unsure if nomogram is useful with this product

• 1 case demonstrated to have biphasic peaks

Signs/symptoms

• Patient has vomited x 6 prior to arrival

• Complaining of GI discomfort

• HEENT: normal

• PEERLA

• Temp 98.9°F

• HR 80, BP 130/78, R 20

Labs

• APAP level 110 mcg/ml at 5.0 hours post ingestion

• ASA level 0

• Tox screen negative for other substances

Calculations

• Patient weighs 85 kilograms

• 11,050 mg APAP was ingested

• 183 mg/kg APAP ingested– Potentially toxic amount in acute od

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

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

Points to remember

• 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

The End