acetaminophen (apap) toxicity: clinical cases, diagnosis, pathology, treatments and patient...

Acetaminophen (APAP)

Poroma BabuEbey Soman

Simardeep Singh

Image from <http://www.straightdope.com/images/art/2000/000929.gif>

References • Acetaminophen: Toxicology Data Network (TOXNET). National Library of Medicine :Hazardous

Substances Data Bank (HSDA), 1 Apr. 1983. Web. 8 Oct. 2010. <http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~ZSagYF:1>

• Moling, Oswald, Cairon, Elena, Rimenti, Giovanni, et al. “Case Report: Severe Hepatotoxicity After

Therapeutic Doses of Acetaminophen.” Clinical Therapeutics 28.5 (May 2006) : 755-760. Web. 6 Oct. 2010.

• Walls, L, CF Baker, and S Sarkar. “Perinatal/Neonatal Case Presentation: Acetaminophen-induced Hepatic Failure with Encephalopathy in a Newborn.” Journal of Perinatology 27.2 (Feb. 2007): 133-136. Web. 6 Oct. 2010.

• Acetaminophen: ChemID Plus Lite. National Library of Medicine :Hazardous Substances Data Bank (HSDA), 1 Apr. 1983. Web. 8 Oct. 2010.

• O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.

• Schaefer, Jeffrey P. "Acetaminophen Intoxication." Dr. Jeffrey P Schaefer, 14 Oct. 2007. Web. 10 Oct. 2010. <http://dr.schaeferville.com/presentations/20071014_acetaminophen_intoxication.pdf>.

• "Focus On: Acetaminophen Toxicity and Treatment." American College of Emergency Physicians. Web. 08 Oct. 2010. <http://www.acep.org/publications.aspx?id=26830>.

Pertinent Abbreviations• APAP – N-acetyl-p-aminophenol

– Active compound of Acetaminophen • NAPQI - N-acetyl-p-benzo-quinone imine

– Toxic Metabolite of Acetaminophen • NAC – N-acetylcysteine • ALT – Alanine Transaminase• AST – Aspartate Transaminase • CpK – Creatine Phosphate Kinase• CrCl – Creatinine Clearance • CYP – Cytochrome P450• ECG – Electrocardiogram• INR – International Normalized Ratio• PT – Prothrombin Time• SrCr – Serum Creatinine

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.

Cases

• Neonatal Case – 4 day-old term male infant – Presents to the ER with episodic

emesis and decreased level of arousal – Prescribed an infant formulation of APAP for pain

after circumcision

Walls, L, CF Baker, and S Sarkar. “Perinatal/Neonatal Case Presentation: Acetaminophen-induced Hepatic Failure with Encephalopathy in a Newborn.” Journal of Perinatology 27.2 (Feb. 2007): 133-136. Web. 6 Oct. 2010.

Image from <http://blogs.babycenter.com/wp-content/uploads/2008/09/images_baby_medicine1.jpg>

Cases• Multiple Risk Case

– 45-year-old male – Presents to the ER with signs of sever hepatotoxicity – Multiple risks for hepatotoxicity related to APAP

• 85kg • Asymtomatic HIV• Hepatitis B virus infection • Hepatitis C virus infection • Chronic use of alcohol• Tobacco and opiate consumption • Malnutrition • Illness-induced starvation

Moling, Oswald, Cairon, Elena, Rimenti, Giovanni, et al. “Case Report: Severe Hepatotoxicity After Therapeutic Doses of Acetaminophen.” Clinical Therapeutics 28.5 (May 2006) : 755-760. Web. 6 Oct.

2010.

Characteristics of Acetaminophen

- White solid crystals - Lightly soluble in cold water - Greater solubility in hot water - Solubility in organic solvents

- Soluble in menthol

Acetaminophen: Toxicology Data Network (TOXNET). National Library of Medicine :Hazardous Substances Data Bank (HSDA), 1 Apr. 1983. Web. 8 Oct. 2010. <http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~ZSagYF:1>

Acetaminophen’s Chemistry • Molecular formula:

– C8-H9-N-O2

• Molecular weight: 151.16• Color/form: large monoclinic

prisms from water • Odor: odorless• Taste: slightly bitter taste • Melting point: 169-170.5°C• Dissociation Constant: pka=

9.38

Acetaminophen: ChemID Plus Lite. National Library of Medicine :Hazardous Substances Data Bank (HSDA), 1 Apr. 1983. Web. 8 Oct. 2010. http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=Search&actionHandle=getAll3DMViewFiles&nextPage=jsp%2Fcommon

%2FChemFull.jsp%3FcalledFrom%3Dlite&chemid=0000103902&formatType=_3D (both image and data)

Acetaminophen’s Pharmaceutical Classes

• Classification – Derivative of acetanilide – Analgesic – Non-narcotic – Antipyretic – DEA Schedule III


Mechanism of Action of Acetaminophen

• Selectively reduces cyclo-oxygenase products in the CNS and PNS – Principally prostaglandins (PG) E2

– As well as other prostaglandins – Thromboxanes – Prostacyclin

Lucas, Ruth, Warner, T.D., Vojnovic, I., and Mitchell, J.A. “Cellular Mechanism of Acetaminophen: Role of Cyclo-oxygenase.” The FASEB Journal 18 (10 Feb. 2005). Web 6 Oct. 2010.

Acetaminophen Mechanism of Toxicity

• APAP is metabolized in the liver – By glucuronidation and sulfation

• At therapeutic doses – 4% converted by the cytochrome P450 into the

reactive toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI)

– NAPQI becomes nontoxic when it binds to glutathione

Moling, Oswald, Cairon, Elena, Rimenti, Giovanni, et al. “Case Report: Severe Hepatotoxicity After Therapeutic Doses of Acetaminophen.” Clinical Therapeutics 28.5 (May 2006) : 755-760. Web. 6 Oct. 2010.

Acetaminophen Mechanism of Toxicity

• APAP overdose occurs due to – CYP enzyme induction – Glutathione depletion – Inhibition of glucuronidation

• If any of the previous actions occur – NAPQI is no longer able to bind to glutathione – Instead, NAPQI reacts with the cysteine group of

hepatocellular proteins – Leads to the loss of cell function and cell death


Acetaminophen Metabolism

Source: "Acetaminophen Metabolism." Wikimedia Commons. Web. 8 Oct 2010. <http://upload.wikimedia.org/wikipedia/commons/1/12/Paracetamol_metabolism.svg

Acetaminophen’s Indication• Analgesic, non-narcotic • Relives mild to moderate pain • Reduces fever• Provides only symptomatic relief • Minimum anti-inflammatory activity • Does not relieve redness, swelling, or stiffness due to

arthritiss • Should not be used as a substitute for aspirin or other

salicylates or NSAIDS the treatment of rheumatoid arthritiss

• Is indicated for the relief of pain due to mild osteoarthritis


Acetaminophen’s Indication• May be used when aspirin therapy is

contraindicated or inadvisable • Used to treat acute-tension type headaches

with mild to moderate pain • Used for mild to moderate myalgia, arthralgia,

chronic pain of cancer, postpartum pain, and postoperative pain


Routes of Exposure

• Most common – Ingestion as an analgesic

for relief from pain

• Other routes – Inhalation and dermal

contact • Usually by workers that

work at places that APAP is produced or used


Image taken from <http://www.clipartheaven.com/show/clipart/health_&_medical/cartoons/taking_medicine_2-gif.html>

Neonatal Case: Route of Administration

• APAP was prescribed by the doctor for the 4-day old term male infant for pain due to circumcision – Every 4h since his circumcision on the 2nd day of his birth

• Total amount of APAP received by the patient – 80mg (26mg/kg) every 4h for the first 24h

• This was while he was still in the hospital – 10mg (13mg/kg) every 4h for the next 2 days

• This was after he was discharged and taken home

• APAP concentration measured 16h after his last dose at home – 109.8µg/ml (therapeutic range 10-30µg/ml)


Multiple Risk Case: Route of Administration

• APAP was self administered by the patient for a rise in temperature to 40°C– 1000mg QID for 4 days – And once during the morning before his admission

to the hospital

• He also took – Single dose of twelve 2mg tablets of

buprenorphine • For withdrawal symptoms


Populations at Risk

• Patients with sulfite sensitivity – Some commercially available formulation contain

sulfites – May cause allergic-type reactions

• Anaphylaxis • Life threatening or less sever asthmatic episode

– This is a low occurrence incidence and usually occurs in asthmatic individuals


Source: WATSON, WILLIAM. "2003 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System" AMERICAN JOURNAL OF EMERGENCY MEDICINE 22.5 (2004): 386. Web. 8 Oct 2010. <http://www.aapcc.org/dnn/Portals/0/AJEM%20-%20AAPCC%20Annual%20Report%202003.pdf>

Neonatal Case

• 4-day term infant


Image from <http://blogs.babycenter.com/wp-content/uploads/2008/09/images_baby_medicine1.jpg>

Multiple Risk Case • 85kg male • Asymptomatic HIV • HBV infection • HCV infection • 20 packs of cigarette daily • 1L of beer daily • IV heroin (4 months prior to his hospital visit)• For the last 4 days before the hospitalization

– Pt starved due to • Fever • Malaise • Nausea


Biological Fate- Usually Acetaminophen is absorbed within 1 hour (IR products, 2 hours for EC products) after ingestion, but many factors can change this:•Drugs affecting GI motility•If the drug itself was taken in another dosage form such as elixirs or liquid preparation•If the tablet was cut or broken before injection

- In children, the rate of absorption is drastically increased. However their chances of hepatotoxicity is lower (unclear)

- Peak Serum concentrations of acute overdose may be delayed by as much as 4 hours

Acetaminohen Structure: Harrison, Kari. "Acetaminophen." 3D Chem. 3D Chem, 01 Jun 2003. Web. 8 Oct 2010. <http://www.3dchem.com/molecules.asp?ID=9>.

NAPQI Structure: "N-acetyl-p-benzo-quinone imine ." N-Acetyl-p-benzochinonimin . Web. 8 Oct 2010. <http://commons.wikimedia.org/wiki/File:N-Acetyl-p-benzochinonimin.svg>.

Acetaminophen (APAP)

N-acetyl-p-benzo-quinone imine (NAPQI)

Acetaminophen: Toxicology Data Network (TOXNET). National Library of Medicine :Hazardous Substances Data Bank (HSDA), 1 Apr. 1983. Web.

8 Oct. 2010. <http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./t

emp/~ZSagYF:1>

Biological Fate (Con’t)• Acetaminophen is metabolized in

the liver in adults primarily (85-90%) by direct sulfation (~30% ) and glucuronidation (~65-75%).

• Another 5% is excreted unchanged in the urine while 5-10% is metabolized by CYP 450 enzymes 2E1, 1A2 and 3A4.

• However N-acetyl-p-quinoneimine metabolite is formed by oxidation via CYP enzymes and it can cause hepatotoxicity in acute doses (necrosis occurs)

• NAPQI is changed via glutathione conjugation and excreted as Mercapturic acid

Excretion differences of Acetaminophen in Children vs. AdultsSource: Kociancic, Todd. "http://www.medscape.com/viewarticle/459187_2." Medscape Pharmacist. Pharmacotherapy Publications Inc, 2003. Web. 8 Oct 2010. <http://www.medscape.com/viewarticle/459187_2>.

Acetaminophen: Toxicology Data Network (TOXNET). National Library of Medicine :Hazardous Substances Data Bank (HSDA), 1

Apr. 1983. Web. 8 Oct. 2010. <http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~ZSagYF:1

>

Children vs. Adults• Children have faster turnover

rate of glutathione or increased sulphate conjugation, hence why they might be less likely to get hepatotoxicity but decreased glucuronidation capacity

• Most cases of child-toxicity are due to unintentional overdose of drug with a therapeutic intent

• Phenylketonuria patients need to be careful with Children’s acetaminophen

• Use weight-based dosing and calibrated dosing equipment!!

• Toxicity data in adults with liver damage is unclear

• Factors discussed previously can predispose adults and children for higher risk of liver damage

• Patients taking anti-coagulants should be monitored for INR levels

• Renal function is another issue most people forget to address

• Fasting patients are high risk since 4g-10g can easily induce hepatotoxicity


General Effects of Toxicity• The classic effect is

hepatotoxicity, can lead to jaundice and increased liver enzymes in the blood

• Liver failure can result in encephalopathy, confusion, coma and ultimately leading to death

• Treatment after acute liver failure can involve liver transplant

• Transient azotemia in most patients, renal failure in some patients

• Hypoglycemia and decreased glucose tolerance in patients (2-4 days after hepatic failure)

• Metabolic acidosis and alkalosis are reported (dec epinephrine response)

• Cerebral edema & nonspecific myocardial depression have also been observed


Effects Continued

• Pulmonary Edema • Myocardial (EKG

changes and CPK M&B changes)

• Nausea & Vomiting followed by abdominal pain and hepatotoxicity

• Hyperamylasemia may be detected in some cases (Pancreatitis)

• Proteinuria and Renal damage (tubular necrosis)

• Hypophosphatemia reported in patients with overdose regardless of liver damage (non survivors?)

• Hemolysis in patients with G6PDH


Teratogenicity• Acetaminophen can cross the

placenta but no harm if therapeutic doses (Category B)

• Maternal toxicity can lead to renal and hepatotoxicity in fetus

• 1st Trimester: Structural damages & spontaneous abortions

• 2nd or 3rd Trimester: Functional damages

• Near Term: fetal anemia and neonatal jaundice

• Early N-acetylcysteine treatment is the key!!

Source: "Two-day old baby with a good case of jaundice." Jaundice (Hyperbilirubinemia). Web. 11 Oct 2010. <http://navelgazingmidwife.squarespace.com/storage/092smsm.jpg?__SQUARESPACE_CACHEVERSION=1270062632364>.

A two day old baby with Jaundice


Toxicogenomics Biomarkers• CYP2D6 is the only non-inducible CYP

enzyme that is HIGHLY polymorphic (over 90 alleles on Chromosome 22) - CYP 2D6*2A allele in ultra-rapid metabolizers = increased NAPQI production

• CYP2E1 Type A is slow (c1/c1 gene), Type B is moderate (c1/c2 gene) and Type C is fast (c2/c2 gene) metabolizer

• But Type C is also has fast elimination rate while type B and type A are slower – patients with type B are at higher risk of CYP2E1 induced NAPQI formation since metabolism is moderately fast and elimination rate is half that of type C patients

• Chronic alcoholism has been linked with increased expression of CYP2E1 and animal studies clearly indicate that this is a MAJOR factor in hepatotoxicity.

Sources: Madadi, Parvaz, et al. "Safety of codeine during breastfeeding." Canadian Family Physician 53.1 (2007): 33-35. Web. 12 Oct 2010. <http://www.cfp.ca/cgi/content/full/53/1/33>. Shuldiner, Alan, Joan Hebert, and Michelle Carillo. "Annotated PGx Gene Information for CYP3A4." PharmGKB. Stanford University , July 2007. Web. 12 Oct 2010. <http://www.pharmgkb.org/search/annotatedGene/cyp3a4/>. Ueshima, Y, et al. "Acetaminophen metabolism in patients with different cytochrome P-4502E1 genotypes." Alcoholism: Clinical and Experimental Research 20.1 (1996): 25A-28A. Web. 12 Oct 2010. <http://www.ncbi.nlm.nih.gov/pubmed/8659683>.

CYP 2E1 Role in Toxicity

Source: "Determination of APAP-induced liver and kidney injury in wild-type and Cyp2e1-null mice." Identification of Novel Toxicity-associated Metabolites by Metabolomics and Mass Isotopomer Analysis of Acetaminophen Metabolism in Wild-type and Cyp2e1-null Mice. Web. 12 Oct 2010. <http://www.jbc.org/content/283/8/4543/F1.large.jpg>.

Secondary Effects• Studies in rat hepatocyte cultures show that

Acetaminophen is not Genotoxic but it can deplete liver glutathione stores and release lactate dehydrogenase in small amounts

• Other studies show that secondary damage to the liver can occur from the inflammatory process of the body.

• A liver damaged by Acetaminophen can undergo apoptosis which can activate Tlr9 and the Nalp3 inflammasome – leading to increased IL-1 and IL-8 production

• More cells undergo apoptosis as a result• Can be treated by Aspirin and Tlr9 antagonists in Rat

studies

Source: Imaeda, Avlin, Watanabe, Azuma, et al. "Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome." Journal of Clinical Investigation 119.2 (2009): 305-315. Web. 11 Oct 2010. <http://www.jci.org/articles/view/35958>.

Tlr9 and Nalp3 Pathways

Source: Imaeda, Avlin, Watanabe, Azuma, et al. "Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome." Journal of Clinical Investigation 119.2 (2009): 305-315. Web. 11 Oct 2010. <http://www.jci.org/articles/view/35958>.

Exposure Risk Assessment

• How much?

• What preparation?

• When?

• Pattern of Abuse?

• Intent?

• Comorbid or Drug use?

Helps determine patient risk factors, a time frame for when the drug was ingested, how much was ingested and enable the health care worker to arrive at a proper diagnosis and treatment


Symptoms

• Occur in Four Stages• Usually minor until 48

hours post-exposure• May not exist for mild

poisoning

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image taken from http://4.bp.blogspot.com/_EQiYy5Raips/TEWsm9LlYPI/AAAAAAAAAcA/KmfU6fMU0N4/s1600/sick_girl.jpg 08 Oct. 2010

Stage 1

• Within 24 hours• Mild • Nausea, Vomiting,

Anorexia

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image taken from http://3.bp.blogspot.com/_w5baxtfyh30/THFIB3T8qvI/AAAAAAAAAZg/sdhqVxj4h60/s1600/nausea.gif. 08 Oct. 2010

Stage 2

• 24-48 hours after exposure

• Right upper quadrant abdominal pain

• Elevated AST, ALT, Bilirubin levels are also possible

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image taken from http://anatomy.med.umich.edu/surface/abdomen/ab_quadrant.jpeg. 08 Oct. 2010

Stage 3

• 72-96 Hours after exposure

• Vomitting• Peaking of AST, ALT

levels• In severe cases

symptoms of Pancreatitis and Nephrotoxicity

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image 1 taken from http://www.merlehamburger.net/images/pancreas2.jpg. 08 Oct. 2010.Image 2 taken from http://www.osovo.com/diagram/diagram-of-kidney.gif. 08 Oct. 2010.

Stage 4

• Over 5 days after exposure

• Two things can occur– Resolution of liver

toxicity– Multiple organ failure

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image taken from http://www.knowyourgut.com/wp-content/uploads/2009/07/emergency-room.jpg. 08 Oct. 2010

Other Consequences of Severe Toxicity

• Hepatic Encephalopathy– Grade III – Confusion– Grade IV – Coma

• Hypoglycemia


Serum Acetaminophen Levels

• Most accurate measure

• Rumack-Matthew nomogram

• Time of exposure required

• Important to get four hour level

Rumack-Matthew nomogram


Neonatal Case

• Symptoms present after being admitted to the hospital – Sleepy /lethargic – Fed poorly – Vomited about 10 times in the last 24 hrs – Moderately dehydrated – Poorly responsive to stimulation


Multiple Risk Case

• Symptoms present upon reporting to the ER– Extreme weakness – Malaise


Patient Assessment (Labs)

Within 8 Hours of Overdose• Lab test to determine serum

acetaminophen levels• Begin Acetylcysteine or other

charcoal treatment as recommended by guidelines

• If Acetylcysteine treatment is given, continue to monitor renal, liver and serum electrolyte levels

• If needed, re-test serum acetaminophen levels (should see an improvement)

Unknown Time of overdose• Lab tests to determine serum

acetaminophen levels• Patient INR levels, Liver

enzyme levels, liver function, renal function (SrCl) and serum electrolyte levels should be determined

• Treat with Acetylcysteine if serum Acetaminophen or transaminases (ALT, AST) are detected

Lab ValuesMeasure Indicative of Toxicity

Serum Creatinine (SrCr) Elevated over 3.4 mg/dL

Creatinine Clearance (CrCl) Lowered

International Normalized Ratio (INR) Elevated

Prothrombin Time (PT) Elevated over 100 seconds

Aspartate Aminotransferase (AST) Elevated

Alanine Transaminase (ALT) Elevated

Billirubin Elevated over 18 mg/dL

O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Schaefer, Jeffrey P. "Acetaminophen Intoxication." Dr. Jeffrey P Schaefer, 14 Oct. 2007. Web. 10 Oct. 2010. <http://dr.schaeferville.com/presentations/20071014_acetaminophen_intoxication.pdf>.

http://www.merck.com/mmpe/sec21/ch326/ch326c.html

Treatment

• Two treatment methods– Activated Charcoal

• Works by adsorbing unabsorbed drug in the stomach

– N-acetylcysteine (NAC)• Works by increasing hepatic

glutathione stores.

Schaefer, Jeffrey P. "Acetaminophen Intoxication." Dr. Jeffrey P Schaefer, 14 Oct. 2007. Web. 10 Oct. 2010. <http://dr.schaeferville.com/presentations/20071014_acetaminophen_intoxication.pdf>.O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image 1 taken from http://wellnessmama.files.wordpress.com/2009/11/221834-main_full.jpg. 10 Oct. 2010Image 2 taken from https://www.lifeluxure.com/images/N-Acetyl-Cysteine.jpg. 10 Oct. 2010

Activated Charcoal

• Must be initiated within four hours of exposure

• Can be given after 4 hours if an extended release formulation of acetaminophen was ingested

Schaefer, Jeffrey P. "Acetaminophen Intoxication." Dr. Jeffrey P Schaefer, 14 Oct. 2007. Web. 10 Oct. 2010. <http://dr.schaeferville.com/presentations/20071014_acetaminophen_intoxication.pdf>.DRUGDEX® System . Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com. 10 Oct. 2010Image 1 taken from http://www.nynaturalhealthcenter.com/vitamins/images/activatedcharcoal1.jpg. 10 Oct. 2010

Given at 1-2 grams per Kilogram Body Weight

N-Acetylcysteine • Must be initiated 8-10 hours

after ingestion • Benefit questionable >24 hours• Oral

– Loading dose 140 mg/kg– Maintenance dose 70 mg/kg every 4

hours for 17 doses• Intravenous (IV)

– Loading dose 150 mg/kg in 200ml D5W over 15 minutes

– Followed by 50 mg/kg in 500 cc D5W infused over 4 hours, then 100 mg/kg in 1,000 cc D5W infused over the remaining 16 hours.

"Focus On: Acetaminophen Toxicity and Treatment." American College of Emergency Physicians. Web. 08 Oct. 2010. <http://www.acep.org/publications.aspx?id=26830>.O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>.Image 1 taken from http://www.kingguide.com/images/vials.gif. 08 Oct. 2010.

Lab Values in the Neonatal Case

• Upon arrival to the hospital – Glucose 27mg/dl (NR: 45-120mg/dl)– Na 149mEq/l (NR: 135-148mEq/l)– K 5.9mEq/l – Cl 110mEq/l (NR: 91-111mEq/l)– CO2 18mEq/l

– BUN 40mg/dl– Creatinine 3.2mg/dl (NR: 0.3-1mg/dl)


Lab Values in Neonatal Case

• Upon arrival in the hospital (con’t)– Total serum bilirubin 9mg/dl with a conjugated

fraction of 1.4mg/dl– Serum ammonium 114µmol/l (NR: 56-92µmol/l )– AST 718IU/l (NR: 20-65IU/l)– ALT 978IU/l (NR: <54IU/l)– PT 51.9s (NR: 10.1-15.9s)– PTT 45.7s (NR: 31.3-54.3s)– INR 5.4 (NR: 0.96-1.04)– D-dimer 5.9mg/l


Lab Values in Neonatal Case• Upon arrival to the hospital (con’t)

– Factor V assay 57%– Fibrinogen 61mg/dl (NR: 1.67-3.09g/l)– WBC count of 13,600/mm2 – Hematocrit 66.4%– Platelets of 154,000/mm3

– Cerebral spinal fluid analysis was normal


Neonatal Case: Treatment

• Initial treatment without knowledge of APAP toxicity – Intravenous volume expansion – Dextrose – Ampicillin – Cefotaxime


Neonatal Case: Progress

• 1st hospital day– Encephalopathy worsened with development of

recurrent seizures


Neonatal Case: Treatment (con’t)

• After understanding that he was showing clinical manifestations of APAP toxicity – 20h intravenous NAC infusion protocol using a

conc. of 40mg/ml in 5% dextrose (to avoid volume overload and hyponatremia)

• Initiated with 150mg/kg bolus of NAC given in 15 min• Followed by a 50mg/kg bolus over 4h • Then 100mg/kg over 16h

– Subsequent doses were given in 100mg/kg aliquots over 16h


Neonatal Case: Treatment(con’t) • Supportive measures

– To correct coagulopathy• Transfusion of fresh frozen plasma • Cryoprecipitate

– Induce diuresis • Fluid boluses • Furosemide

– For blood-tingled gastric aspirates• Ranitidine

– To cause increase stooling • Enteral lactulose therapy

– Change in diet • High dextrose • Restricted protein


Lab Values in Neonatal Case: After Treatment

• Within 2 days and 4h – APAP gradually decreased to <10µg/ml after the last dose given at

home • By the 3rd day of treatment

– Coagulation profile normalized – Liver and renal function improved– PT 12.4s– PPT 44.7s – INR 1.2 – Factor V assay 93%– Fibrinogen 290mg/l– AST 107IU/l– ALT 326 IU/l – Serum bilirubin 2.4mg/dl with a conjugated fraction of 0.6mg/dl – Serum creatinine 0.4mg/dl


Neonatal Case: After Treatment

• Pt was released on the 7th hospital day• 9 months after his release

– He was developing without any apparent long-term effects


Lab Values in Multiple Risk Case

• Upon entering the ER– AST 6472 IU/l– Serum L-lactate dehydrogenase (LDH) – Bilirubin 2.3mg/dL

• 8hrs after entering the ER– Liver enzymes became worse – AST 8581 IU/l– Serum ALT 5433 IU/l– LDH 13,641 IU/l– Prothrombin INR 2.15


Multiple Risk Case: Treatment

• IV administration was started immediately – 150mg/kg for the first 90 mins– 50mg/kg q4h for the next 3 days

• Supportive Measures – 3 units of plasma – Afterward central venous catheter was inserted – Continuous IV infusion with 2L of 20% glucose

solution with electrolytes – 500ml of a solution containing branched-chain amno

acids, vitamin K, sucralfate, and methadone


Multiple Risk Case: After Treatment

• APAP blood level was 0.4mg/L• AST 42 IU/l• ALT 209 IU/l• LDH 310 IU/l• Prothrombin INR 2.56 mg/dL• Bilirubin 4.4mg/dL• CD4 T-cells 288/mm3

• HIV-RNA 2.560 copies/mL


Comparison of Routes of Administration

Oral (PO) Intravenous (IV)

Low Cost High Cost

Long duration of therapy (72 hours) Shorter duration of therapy (20 hours)

Adverse Effects are minimal Usually Nausea and Emesis

More Adverse Effects AnaphylactOID Reaction (No IgE action)

Vomiting <1hr post-administration requires the dose to be readministered

Adverse effects more common in asthmatic patients

Poor palatability Rash, Itching, Bronchospasm, Tachycardia, Hypotension

Patients that are not candidates for oral route have to use IV

Symptoms are usually mild (severe in ~1% of cases)

Ex. Neonates, Patients with altered mental status, GI bleed, repeat vomiting etc.

Hold infusion and re-challenge with lower dose (Low recurrence rate)

"Focus On: Acetaminophen Toxicity and Treatment." American College of Emergency Physicians. Web. 08 Oct. 2010. <http://www.acep.org/publications.aspx?id=26830>.O'Malley, Gerald F. "Acetaminophen Poisoning: Poisoning: Merck Manual Professional." Merck & Co., Inc. Merck & Co. Web. 08 Oct. 2010. http://www.merck.com/mmpe/sec21/ch326/ch326c.html>."Clinical Policy: Critical Issues in the Management of Patients Presenting to the Emergency Department with Acetaminophen Overdose." National Guideline C

Clearinghouse. US Department of Health and Human Services, 15 Feb. 2008. Web. 10 Oct. 2010. <http://www.guideline.gov/content.aspx?id=11428&search=acetaminophen+overdose>.

Article Title: Incidence of adverse drug reactions induced by N-acetylcysteine in patients with acetaminophen overdose.Diagrammatic representation of adverse drug reaction (ADR) profiles in patients treated with intravenous N-acetylcysteine (IV-NAC) versus without treatment for acetaminophen overdose, categorized by ADR severity: mild-moderate-severe.

Human & Experimental Toxicology, Mar2010, Vol. 29 Issue 3, p153-160, 8p, 1 Diagram, 3 Charts, 1 GraphDiagram; found on p155

Article Title: Incidence of adverse drug reactions induced by N-acetylcysteine in patients with acetaminophen overdose.

Number of different adverse drug reactions occurred after receiving the recommended dose of intravenous N-acetylcysteine among patients with acetaminophen overdose (N = 125).

Human & Experimental Toxicology, Mar2010, Vol. 29 Issue 3, p153-160, 8p, 1 Diagram, 3 Charts, 1 GraphGraph; found on p157

Patient Education• Patient should not take over 4

grams of Acetaminophen/day.• Threshold may be lower for

patients with liver disease or cirrhosis

• Increased risk of hepatotoxicity with chronic alcohol use

• Patient should be careful when taking numerous products containing Acetaminophen – Ideally this should be avoided

DRUGDEX® System . Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com. 10 Oct. 2010Image 1 taken from http://blog.oregonlive.com/health_impact/2009/07/acetaminophen.JPG. 10 Oct. 2010

Neonatal Case: What Went WRONG

• Patient Education (or in this case it is the parent education)– The parents did not administer the drug based on

any signs of pain – They simply believed that APAP was not harmful – They were simply instructed by the hospital

personnel to administer the drug every 4h – They should have been advised that 24h after

circumcision, APAP should not be administered unless there is evidence of pain


Acetaminophen Containing Products• Prescription Drugs

– Darvocet® – Endocet® – Fioricet® – Hycotab – Hydrocet® – Hydrocodone Bitartrate – Lortab® – Percocet® – Phenaphen® – Sedapap® – Tapanol® – Ultracet® – Vicodin® – Zydone®

• Over the Counter Drugs– Actifed® – Anacin® – Benadryl® – Cepacol® – Contac® – Coricidin® – Dayquil® – Dimetapp® – Dristan® – Elixir® – Excedrin® – Feverall® – Formula 44® – Goody’s® Powders – Liquiprin® – Midol® – Nyquil® – Panadol®

Robitussin® Saint Joseph® Aspirin-Free Singlet® Sinutab® Sudafed® Theraflu® Triaminic® TYLENOL® Brand Products Vanquish® Vicks® Zicam® These are only the commonly used products.

There are many other products available.

"Acetaminophen (APAP) & Liver Damage." TYLENOL® - The Official Website for All TYLENOL® Products. McNeil INC. Web. 08 Oct. 2010. <http://www.tylenol.com/page.jhtml?id=tylenol/news/acetaminophen_liver_damage.inc>.

Summary

• Do the Exposure Risk Assessment, evaluate patient labs• If less then 4 hours after exposure, try treating the

patient with activated charcoal• If Serum Acetaminophen levels are detected, treat with

Acetylcysteine and monitor patient liver function, renal function, INR and serum acetaminophen levels

• If liver failure occurred, do necessary therapy to return function or consider liver transplant as a option

• Advice patient on how to avoid toxicity in the future and if the patient was in the high risk group, how the patient can reduce the risk of toxicity

Summary Video

Source: "Toxicity of Acetaminophen and Salicylates - USMLE Study Songs." YouTube Channel - StudyWithSubstanceP. Web. 12 Oct 2010. <http://www.youtube.com/watch?v=NepKOh5JrfE>.

acetaminophen (apap) toxicity: clinical cases, diagnosis, pathology, treatments and patient...

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