Mechanisms of Hepatotoxicity

Mechanisms of
Hepatotoxicity
Reza Heidari
Pharm.D and Toxicology PhD
Pharmaceutical Sciences Research Center
Shiraz University of Medical Sciences

Introduction
Liver plays a key role in detoxifying harmful
substances that you may eat, drink, inhale or rub
on your skin. Toxic hepatitis is liver inflammation
that occurs when your liver is damaged by toxic
chemicals, drugs or certain poisonous
mushrooms.

• After absorption into the systemic circulation
and distribution throughout the body :
localization of toxicity in distinct tissues

Located in the right upper quadrant of the abdominal
cavity, resting just below the diaphragm. The liver lies to
the right of the stomach and overlies the gallbladder.

Factors Influencing Susceptibility
1. Toxicokinetic factors : accumulation of high
concentrations of a xenobiotic
Well-perfused organs or tissues – those that receive
strong blood flow – can also readily accumulate
blood-borne toxicants. These considerations are
especially important for the liver and kidneys –
which as major excretory organs necessarily
receive a high blood flow while also strongly
expressing many xenobiotic transporters.

Factors Influencing Susceptibility
2. Metabolic fate of a chemical: high-level
expression of xenobiotic-metabolizing enzymes

Mechanistic Toxicology
The molecular basis of how chemicals disrupt biological targets, Urs A. Boelsterli
Head, HepaTox Consulting
Pfeffingen, Switzerland

Mechanism of Liver Damage
• Due to its unique metabolism and close relationship
with the gastrointestinal tract, the liver is susceptible to
injury from drugs and other substances.
• 75% of blood coming to the liver arrives directly from
gastrointestinal organs and then spleen via portal veins
which bring drugs and xenobiotics in concentrated
form.
• Injury to hepatocyte and bile duct cells lead to
accumulation of bile acid inside liver. This promotes
further liver damage.

• Several mechanisms are responsible for either
inducing hepatic injury or worsening the damage
process.
• Many chemicals damage mitochondria, an
intracellular organelle that produce energy.
• Its dysfunction releases excessive amount of
oxidants which in turn injures hepatic cells.
• Non-parenchymal cells such as Kupffer cells, fat
storing stellate cells and leukocytes (i.e.
neutrophil and monocyte) also have role in the
mechanism.

Signs and symptoms:
• Yellowing of the skin and whites of the eyes
(jaundice)
• Fatigue
• Loss of appetite
• Nausea and vomiting
• Weight loss
• Dark or tea-colored urine

AGENTS WHICH CAUSE OF LIVER DAMAGE
• Toxins - Drugs, Chemicals, Fe,Cu, alpha-1-AT.
• Ischaemia - venous or arterial thrombosis,
hypertension.
• Infection - viral,protozoal, bacterial.
• Immunological - autoimmune, response to infection.
• Cholesterol or triglycerides can accumulate (such as
in steatosis; steat=fat + osis=accumulation).
• Obstruction of bile flow (such as in cholestasis:
chole=bile + stasis=standing).

Drugs causing Liver damage
• Acetaminophen:-
(Paracetamol, also known
by the brand name Tylenol
and Panadol) is usually well
tolerated in prescribed dose
but overdose is the most
common cause of drug
induced liver disease and
acute liver failure
worldwide. Acetaminophen (3D structure)
overdose is the most common cause
of drug induced liver disease

 Nonsteroidal anti-inflammatory drugs- Aspirin,
ibuprofen, sulindac, phenylbutazone, piroxicam,
diclofenac and indomethacin.
 Glucocorticoids- Glucocorticoids are so named due to
their effect on carbohydrate metabolism. They promote
glycogen storage in liver. The classical effect of prolonged
use both in adult and pediatric population is steatosis.
 Isoniazid- Isoniazide (INH) is one of the most commonly
used drug for tuberculosis; it is associated with mild
elevation of liver enzymes in up to 20% of patients and
severe hepatotoxicity in 1-2% of patients

• Natural products- Amanita
mushroom, particularly the
destroying angels, aflatoxins.
• Industrial toxin- Arsenic,
Carbon tetraChloride, Vinyl
Chloride.
• Herbal and alternative
remedies- Ackee fruit,
Camphor, Pyrrolizidine
alkaloids, Valerian, Comfrey
(often used in herbal tea).

Forms of liver toxicity:-
 Tissue Necrosis-
 Hepatitis- Disease of the liver causing
inflammation.
 Cholestasis- Cholestasis is a condition where bile
cannot flow from the liver to the duodenum.
 Steatosis- Steatosis is a condition characterized
by the build up of fat within the liver, sometimes
triggering inflammation of the liver

• Granuloma- A granuloma is one of a number
of forms of localized nodular inflammation
found in tissues.
• Vascular lesions- They result from injury to
the vascular endothelium.
• Neoplasm- Neoplasm or tumor, tissue
composed of cells that grow in an abnormal
way.

Complications:-
Except for gallstone disease and some viral infections
such as Hepatitis A and infectious mononucleosis, most
liver diseases are managed and not cured.
Liver disease can progress to cirrhosis and liver failure.
Associated complications may include increased risk of
bleeding and infection, malnutrition and weight loss, and
decreased cognitive function.
Some liver diseases are associated with an increased risk
for developing liver cancer

CELLULAR TARGETS OF LIVER DAMAGE
• HEPATOCYTES - Paracetamol toxicity;Viral Hepatitis
• BILE DUCTS - Primary Biliary Cirrhosis, Sclerosing
Cholangitis.
• ENDOTHELIAL CELLS - Drugs.

Treatment:-
 No specific treatment exists for most kinds of toxic
hepatitis
For most other cases of drug-induced toxic hepatitis,
stopping the medication is the only treatment.
Other treatments include:
 Supportive therapy. People with severe symptoms are
likely to receive supportive therapy in the hospital,
including intravenous fluids and medication to relieve
nausea and vomiting.
 Liver transplant. When liver function is severely impaired,
a liver transplant may be the only option for some people

Acetaminophen’s Chemistry
• Molecular formula:
– C8-H9-N-O2
• Molecular weight: 151.16
• Color: White
• 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)

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’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
arthritis
• Should not be used as a substitute for aspirin or other
salicylates or NSAIDS the treatment of rheumatoid
arthritis
• Is indicated for the relief of pain due to mild
osteoarthritis
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 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, and postoperative pain

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

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/car
toons/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)
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.

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>

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?./temp/~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. Adults
Source: 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-

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

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>
.

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
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
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
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
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
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>.

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
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.

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 Values
Measure 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
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>.

Treatment
• Two treatment methods
– Activated Charcoal
• Works by adsorbing
unabsorbed drug in the
stomach
– N-acetylcysteine (NAC)
• Works by increasing hepatic
glutathione stores.
Image 1 taken from http://wellnessmama.files.wordpress.com/2009/11/221834-main_full.jpg. 10 Oct. 2010
Image 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
DRUGDEX® System . Thomson Reuters (Healthcare) Inc. http://www.thomsonhc.com. 10 Oct. 2010
Image 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>.
Image 1 taken from http://www.kingguide.com/images/vials.gif. 08 Oct. 2010.

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>.
"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>.

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. 2010
Image 1 taken from http://blog.oregonlive.com/health_impact/2009/07/acetaminophen.JPG. 10 Oct. 2010

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>.

References
• Wikipedia:
http://en.wikipedia.org/wiki/Liver_disease
• Medicine Net:
http://www.medicinenet.com/liver_disease/articl
• Robbins Basic Pathology
• Google Images

Mechanisms of Hepatotoxicity

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