Acetaminophen

N-acetyl-P-aminophenol
)APAP(

Dr. Nayira A. Abdel Baky

Associate Professor
Pharmacology and Toxicology
 ACETAMINOPHEN
Acetaminophen is contained in more than 100 over-the--
counter drug preparations and is routinely reported as the
.most common pharmaceutical agent involved in overdose

Acetaminophen was fourth among the top 25 substance-

.categories with the highest number of fatalities (208 cases)

Hepatic failure due to acetaminophen overdose the most-

common cause of liver failure requiring transplantation in
.the United Kingdom and in the United States

Acetaminophen toxicity is an example of saturation of-

.deactivation pathways
 ACETAMINOPHEN
Therapeutic dose = 4 gm/24 hour in adults and 90mg/kg in -
childeren

As little as 7.5g can be toxic (exceptions: patients who are taking

enzyme inducer as anticonvulsants or rifampin, patients with
history of chronic ethanol abuse, fasting, malnutrition, or HIV
.infection or patient with reduced ability to conjugate toxin

The safety of acetaminophen depends on the availability of -

antioxidant such as reduced glutathione (GSH) and other
.thiol-containing substances required to detoxify NAPQI
Met pathways of APAP
Under normal metabolic conditions and recommended doses

Hepatic glucuronide conjugation(40-65%)

Hepatic glucuronide conjugation(40-65%) -1
Hepatic sulfat conjugation(20 - 45%)
Hepatic sulfat conjugation(20 - 45%)
.inactive metabolites excreted in the urine 91-93%

.Excretion of unchanged APAP in the urine (2%) -2

Oxidation by cytochrome P450 to NAPQI (5%) -3

 GSH combines with NAPQI
 nontoxic cysteine/mercaptate conjugates
. excreted in urine
Mechanism of Toxicity
The ingested APAP undergo oxidative metabolism
by CYP- 450 to reactive intermediate metabolite
(N-acetyl –P-benzoquinone imine=NAPQI) which is
rapidly bounded to glutathion ,detoxified through
conjugation pathway ,and excreted. In the presence of
adequate GSH stores , there is no fear from any toxicity.
However, overdose of APAP saturate the conjugation
pathways and NAPQI overwhelms the GSH detoxifi-
cation mechanism , finally leading to liver necrosis and
.may be death
Acetaminophen Metabolism
Glucuronyl
transferase Sulf otransferase
:In Other Words
If too much acetaminophen is around
Saturation of glucuronidation and sulfation pathways-1
.Amount of APAP metabolized by p450 cytochromes to NAPQI increases-2
Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol-3
.containing substances
:In OD-4
Rate and quantity of NAPQI formation overwhelms GSH supply and
:regeneration (glutathione levels fall to less than 30% of normal)
 elimination of NAPQI prolonged
 free NAPQI binds critical intracellular proteins with sulfhydryl groups
(hepatocyte membranes)
.  cellular dysfunction and cell death and liver necrosis
Renal toxicity
Organ dysfunction results everywhere in the body-
where local oxidative metabolism (via CYP-450)
creates NAPQI that cannot be detoxified  direct
.organ toxicity

Cytochrome P-450 enzymes produce NAPQI in the renal -

tubules  NAPQI binds cellular macromolecules  acute
.tubular necrosis

of hepatotoxic cases Hepatorenal Syndrome 25%-

&Volume depletion
Other organs damaged
Heart  myocarditis-
Pancreas  pancreatitis-

It is controversial whether these entities are part -

of multisystem organ failure (MSOF) either from
i-Fulminant hepatic failure (FHF)
.ii- Local accumulation of toxic metabolites
Factors which adversely affect
APAP metabolism
Toxicity is increased in patients with induction of the P450 system-
through drugs such as smooking, rifampicin, phenobarbital,
. isoniazid, phenytoin, carbamazepine

Drugs such as sulfa and AZT (zidovudine) potentiate acetaminophen-

hepatotoxicity by competing for glucuronidation pathways resulting in
- increased cyp2E1-dependent metabolism of acetaminophen

This also occurs in patients with low glutathione reserves, as a-

:product of
Genetic variation-
HIV +ve-
Malnutrition, or fasting-
Alcohol-related or other liver disease-
GSH stores
Glutathione stores are Glutathione replacement by
:determined by :sulfhydryl compounds
Age- Eating-
Diet- NAC-
Liver disease-
Fasting prior ingestion-
Chronic malnutrition-
Anorexia-
Gastroenteritis-
Chronic alcoholism-
HIV-
History & clinical presentation
The course of acetaminophen toxicity generally is divided-
into 4 phases. Clinical evidence of end-organ
(hepatic , occasionally renal) toxicity is often delayed 24
.hours post-ingestion

Because antidotal therapy is most effective when initiated-

within 8 hours post-ingestion, the clinician must obtain
an accurate history of the time(s) of ingestion, the
quantity, and formulation of acetaminophen ingested,
and any co-ingestants, which may delay APAP
.absorption (eg, anticholinergic drugs or opioids)

Because a patient's history may be inaccurate, the serum-

acetaminophen concentration is important for diagnosis
and treatment, even in the absence of symptoms. After a
single ingestion, APAP antidote (NAC therapy) is guided
.by the serum APAP concentration
 Clinical presentation
Phase 1 (few hrs after ingestion up to 24 hr) : Malaise , nausea , vomiting
.and diaphoresis

are peaking),Phase 2 (24-72 hrs after ingestion) : Increase in liver enzymes (transaminases
serum bilirubin , prothrombin time are increased , and pain in the right upper abdominal
.quadrant

Phase 3 (72-96 hrs after ingestion) : Hepatic necrosis is characterized by; peak in the liver
function, altered consciousness, hypoglycemia, jaundice , and coagulation abnormalities
(coagulopathy), and encephalopathy. Hepatic failure can develops in 4th or in the 5th day if
.hepatic damage is sever and death can occcur
Myocardial necrosis, pancreatitis , heamolytic anemia and skin rashes may develop but are
.rare

Phase 4 (96 hours-14 days after ingestion) : Resolution of liver dysfunction and liver enzymes
abnormalities reaching resolution, and healing of the pathologic liver damage. If hepatic
damage is massively sever, sepsis and death may occure at 5-10 days
 Diagnosis
In patient with a history of acetaminophen overdose, a serum acetaminophen -
.level should be measured between 4 and 24 hours after ingestion

The value obtained should be evaluated according to the Rumack-Matthew -

.nomogram for determining the risk of hepatotoxicity and need for therapy

Rumack-Matthew nomogram is semi-logarithmic plot of plasma acetaminophen-

levels vs. time. It is based only on acute ingestion. This nomogram assumes
that acetaminophen absorption is completed by 4 hours and that elimination
.occurs with a half-life of 4 hours

Acetaminophen levels are measured ≥ 4hrs after ingestion and 4 hrs later; if-
either level is above the Rumack-Matthew line of toxicity, treatment is
.required
Laboratory analysis
.Determination of plasma APAP level-1

Monitoring liver profile including serum ALT, AST ,-2

bilirubin , glucose , prothrombin time, platelet count…etc

Determination of kideny functions by measuring plasma -3

.creatinine and BUN

.ECG for assessment of myocardial injury-4

.Urine analysis -5
Management Steps
General measures
If the patient is presented to ER within 4 hrs of ingestion
Gastric lavage-
Activated charcoal ,cathartics (saline sulfate are prefered to enhance sulfate-
.metabolic pathway)
Glucose, bicarbonate, Vit K for elevated prothrombin time-

hours 8<
Take level of APAP after four hours (Peak concentration at 4 hrs then hepatic metabolism)-
Start N-aceylcysteine (antidote) if APAP concentration is high =APAP is-
.on or above nomogram line
When NAC is administered anytime within 8 hours of ingestion, it is nearly 100 % protective-
against hepatotoxicity. Therefore, NAC should be given whenever a potentially toxic
- acetaminophen level is measured above the line on the nomogram

Patients should be advised to return to hospital if vomiting or abdominal pain develop

.or reoccur
Patients with enhanced risk ( on B line)
Patients who regularly consume alcohol in excess-

.Those who are malnourished-

Those who regularly take enzyme-inducing drugs (e.g.-

carbamazepine, phenytoin, phenobarbitone, primidone, St
John's Wort and rifampicin)

Those with conditions causing glutathione depletion (e.g.-

malnutrition, eating disorders, malabsorption states and
HIV infection)

Those people may be at higher risk of liver damage even from

lower plasma paracetamol concentrations than others. The
plasma paracetamol concentration for such patients should
.be considered in relation to treatment line B on the graph
 Nomogram

Normal treatment line

Start N-acetylcysteine (NAC) if Paracetamol level at 4 hours above the treatment line.
However start treatment with NAC immediately - do not wait for the level - if
:any of the following are present
.If more than 150 mg/kg (or 12g in an adult) of paracetamol has been ingested -1
.Or the overdose is staggered-2
.Or the patient is a late presenter (>15hrs post ingestion) having already taken a significant overdose -3
If the patient has taken a significant overdose (based on the history), but the initial Paracetamol level is -4
.below the treatment line then repeat the level four hours later as there can be delayed absorption
 Cont.;Management
hours 8>
Urgent action required because the efficacy of NAC
declines progressively from 8 hours after the
overdose
Therefore, if > 150mg/kg or > 12g (whichever is the
smaller) has been ingested, start NAC immediately,
without waiting for the result of the plasma
paracetamol concentration
hours 24>
Still benefit from starting NAC
Acetaminophen hepatotoxicity antidote
.The antidote is N-acetyl cysteine (NAC) (Mucomyst)-

:NAC acts as antidote through several mechanisms including-

i-It acts as a precursor to cysteine, and then to glutathione, repleting glutathione store

.ii-It provides sulfhydryl donors to which NAPQI can bind and be detoxified

iii-It may also enhance sulfation of any remaining acetaminophen resulting in the
.reduction in the amount of NAPQI that is produced

iv-It has also been shown to improve survival in patients with hepatic failure by acting
as a free radical scavenger, enhancing oxygen uptake and utilization in peripheral
.tissues, including the brain, and by improving microcirculation
?How is NAC administered
The NAC protocol (orally): 140 mg/kg loading dose, followed by 17 doses of -
70 mg/kg administered every 4 hours for a total of 1330 mg/kg over 72
.hours

NAC solution should be diluted from the 20% solution to a 5% solution in -

juice or a carbonated beverage to maximized palatability. It stills smells
.and tastes pretty bad

Vomiting frequently complicates oral NAC administration, and antiemetics -

such as high-dose metoclopramide, up to 1-2 mg/kg, and ondansetron
.may be necessary to help the patient retain the NAC

.Slow instillation through a nasogastric tube may also aid in NAC retention -

Intravenous NAC protocols: (1) 150 mg/kg of IV NAC over 15 minutes; -

this is followed by 50 mg/kg IV over 4 hours, followed by 100 mg/kg over
16 hours. (2)140mg/kg IV over 1 hour followed by 12 doses of 70 mg/kg
.administered every 4 hours
What should I do with a patient with a “chronic”
?ingestion of acetaminophen over several days
The nomogram is meant just for single acute overdose and does not-
apply in the setting of multiple supra therapeutic doses of
.acetaminophen

Evaluation of these patients includes assessment of hepatotoxicity-

(elevated aspartate aminotransferase [AST], alanine
aminotransferase [ALT], PT, and international normalized ratio
.[INR], as well as the presence of any unmetabolized acetaminophen

NAC treatment should be initiated if acetaminophen is still measurable-

or there is evidence of hepatotoxicity and should be continued until
at least 24 hours after the last dose of acetaminophen or until the
.patient is improved
Special considerations for a pregnant
patient and children
Acetaminophen has been shown to cross the placenta and to cause-
hepatotoxicity in a fetus, which has functioning mixed-function oxidase
.liver enzymes (14-16 weeks)

Pregnant patient should receive NAC for treatment with no delay. Delay-
.may associate with fetal death

Children may fare better after ingestion of acetaminophen because of an-

.enhanced capacity for sulfation in their livers

It was suggested that using 2-hours acetaminophen levels to predict-

toxicity risk in children after the ingestion of liquid acetaminophen
.formulas