Transcript Tylenol and Hepatotoxicity - Pro Pharma Pharmaceutical

Tylenol and
Hepatotoxicity
Emmanuelle Mirsakov
Pharm.D. Candidate 2007
USC School of Pharmacy
11-23-06
Importance

Acetaminophen (Tylenol) [APAP] is a common
constituent of OTC (over the counter) pain relievers
 Prescription pain relievers often come in combination
with APAP (e.g. Vicodin (hydrocodone and APAP))
 Current guidelines set the maximum adult daily dose
of APAP to 4g/day (3g/day for elderly)
 Overdosing on acetaminophen is easier than with
other pain relievers. Exceeding the max by only 20
percent for even one day can result in liver injury and
rapidly deteriorating liver function in healthy people;
the kidneys can also be affected.
Mechanism of Action

Despite massive experimental literature, and
the detailed understanding of the mechanism
of APAP’s toxic effect, some aspects still are
controversial and unclear.
 The controversy:
– There have been cases of liver damage from
normal doses (<4g/day) of APAP
Mechanism in a Nut Shell
Background

Cytochrome P450 enzymes (liver metabolism)
 Enzymes in the liver chew up drugs for
removal from the body
 Liver injury not due to drug itself but to the
formation of a toxic metabolite ( a by-product)
 Toxic metabolite: N-acetyl-p-benzoquinine
imine [NAPQI]
Mechanism in a Nut Shell
Normal

Majority of APAP is broken down (metabolized) by a
process called glucoronidation [adding sugar groups
on to detoxify the substance] & Sulphation [ adding
sulfate groups on]; excreted as urine
 A small fraction of APAP is metabolized (broken
down) by the liver (CytP450 enzymes), producing the
toxic metabolite.
 Normally we have a substance called glutathione
(GSH) in our liver (stored there).
 GSH combines with the toxic metabolite to detoxify
it and help it leave the body
Mechanism in a Nut Shell
When Things Go Bad

When there is more toxic metabolite than GSH
then damage to the liver can happen
(hepatotoxicity)
– Controversial as to why/how
– In addition, the imbalance alone is not
enough to cause the damage, but is a
necessary pre-requisite.
Mechanism in a Nut Shell
When Things Go Bad

What can cause this imbalance? (genetic
factors)
– Baseline of GSH in the liver
– Level of liver enzymes to produce the
metabolite
** The dose of APAP that will lead to damage
is variable and unpredictable from patient to
patient
Mechanism in a Nut Shell
When Things Go Bad

What can cause this imbalance? (external
factors)
– Overdose
– Drug interactions (Isoniazide)
– Long-term alcoholism
– Fasting/poor nutrition
Overdose

Too much APAP ingested; more NAPQI byproduct produced
 NAPQI leads to liver damage (attacks the liver
cells)
Overdose
Four Mistakes Account for Most Overdoses of
Acetaminophen:
1.
2.
3.
4.
Acetaminophen is in so many products that many
people exceed the recommended dose by
inadvertently taking two of them together.
Thinking that “more is better,” many people
purposely take more than the recommended dose or
take the next dose too soon after the previous one.
Many people combine acetaminophen with alcohol.
Alcohol increases production of the enzyme that
makes acetaminophen toxic to the liver. If you
drink alcohol and take acetaminophen you can
overdose even at recommended doses.
Many people continue taking Tylenol for longer
than recommended
Rescue for Overdose

N acetylcysteine (NAC) [Acetadote]
– Given within 8 hours of APAP dose, the mortality is zero
– Given within 24 hours it still has some beneficial effects
– How does it work?
 Unknown; thought to act by providing substrate for
conjugation with the toxic metabolite
– Other uses:
 Mucolytic therapy in patients with abnormal or viscid
mucous secretions
Drug Interaction

Isoniazid {treatment of tuberculosis}
– Activates the liver enzymes (specifically:
Isoniazid is an inducer of CYP 2E1)
– So more toxic metabolite is formed and the
GSH is depleted and can no longer
inactivate the increased amounts of NAPQI
– The NAPQI attacks the liver cells and leads
to cell death
Long-Term Alcoholism
 Long-term
alcohol consumption induces
the CYP2E1 enzyme system, leading to
more production of NAPQI
Fasting/Poor Nutrition
 Fasting
has been shown to deplete hepatic
(liver) GSH stores
 Hepatotoxicity has been observed in
fasting individuals after intake of APAP
in modest overdoses
Some Common Tylenol Products
OTC
Tylenol
Excedrin
Pamprin
Cold/cough
preparations:
1)NyQuil
2)DayQuil
RX
Vicodin
Norco
Fioricet
Endocet
Lortab
Percocet
Darvocet
* For a more extensive list please refer to attachment at the end of the handout
Duty of a Health Care Provider
 Educate
patients and fellow health care
providers about products that contain
Tylenol and factors that can increase the
risk of toxicity
 Do not exceed 4g/day; <3g/day for the
elderly
 Look for risk factors (poor nutritional
status, abuse potential, alcoholism,
polypharmacy)
Duty of a Health Care Provider

Educate minority groups and elderly about
Tylenol products and their dangers
– These patient populations are more likely to
buy OTC medications and self-treat
 Recognize depressed patients (look for
complaints of pain with no source causing it;
suicidal ideation)
Conclusions





Tylenol is not a benign pain killer
It is found in combination with many products
Tylenol toxicity can happen at “safe” doses, esp. if
there are additional risk factors
Education of patients and providers is essential
Be a good friend, educate your loved ones about the
dangers of Tylenol
No Joking Matter


Acetaminophen is the active ingredient in more
than 400 over-the-counter (OTC) and prescription
products—including Tylenol and other analgesics
(pain relievers), cough medicines, and sleep aids.
Each year, overdoses of acetaminophen account
for more than 56,000 emergency room visits and
an estimated 458 deaths from acute liver failure,
reports a recent issue of the Harvard Women's
Health Watch.