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Paracetamol , also known as acetaminophen or
APAP (N- acetyl-p-aminophenol)
It is a deethylated active metabolite of phenacetin
discovered in 1877 , which was used as an
analgesic and antipyretic and is banned now
because of its analgesic abuse nephropathy.
In 1893, was first discovered in the urine of
individuals who had taken Phenacetin.
In 1950, Paracetamol tablets were in introduced
By 1963, Paracetamol was available worldwide
To date mechanism of action is not completely
The main mechanism proposed is the inhibition of
cyclooxygenase(COX) and recent findings suggest
that it is highly selective for COX-2.
By inhibition of COX it prevents generation of
prostaglandins from arachidonic acid, which are inturn
converted to numerous other proinflammatory
Poor inhibitor of prostaglandin synthesis in the
peripheral tissues but a potent COX inhibitor in the
By Central subcortical action raising the pain
threshold it raises pain threshold – Acts as an
Good and promptly acting anti pyretic by reducing
has negligible antiinflammatory action - inability
to inhibit COX in the presence of peroxides which
are generated at sites of inflammation, but are not
present in the brain.Good and promptly acting
The ability of paracetamol to inhibit COX-3 could
also account for its analgesic-antipyretic action.
does not stimulate respiration or affect acid-base
does not increase cellular metabolism.
does not affect platelet function or clotting factors
and is not uricosuric.
Plasma t½ is 2–3 hours. Effects after an oral dose
last for 3–5 hours.
Available as IR(immediate release) – 325mg and
500mg doses , ER(extended release) – 650mg
Formulations and preparations – Elixirs,
suspensions, tablets(meltable and chewable),
capsules, rectal suppositories
Opioids - codein, tramadol, etc..
NSAIDS – Mephanamic acid,
MECHANISM OF TOXICITY
A small proportion of acetaminophen is
metabolized by a phase I reaction to a
hepatotoxic metabolite formed from the parent
compound by the cytochrome P450 CYP2E1.
This metabolite, N-acetyl-p-benzoquinoneimine
(NAPQI), is detoxified by binding to
“hepatoprotective” glutathione to become
harmless, water-soluble mercapturic acid, which
undergoes renal excretion.
When excessive amounts of NAPQI are formed,
or when glutathione levels are low, glutathione
levels are depleted and overwhelmed, permitting
covalent binding to nucleophilic hepatocyte
macromolecules forming acetaminophen-protein
The binding of acetaminophen to hepatocyte
macromolecules is believed to lead to
centrilobular hepatic necrosis
Even in the absence of hepatotoxicity, renal
failure can occur because of renal papillary
Large doses act on brain stem and cause rapid
Phase I (0-24 h) Anorexia, nausea, vomiting
Phase II (24-72 h) Right upper quadrant pain,
elevated liver enzymes, PT and INR may be
Phase III (72-96 h) Vomiting, symptoms of liver
failure, renal failure and pancreatitis may occur
Phase IV (>4 days) Resolution of symptoms or
progression to fatality
Acetaminophen causes dose-related centrilobular
hepatic necrosis after single-time-point ingestions, as
intentional selfharm, or over extended periods, as
unintentional overdoses, when multiple drug
preparations or inappropriate drug amounts are used
daily for several days, e.g., for relief of pain or fever.
In these instances,8 g/d, twice the daily
recommended maximum dose, over several days can
readily lead to liver failure.
Use of opioid-acetaminophen combinations appears
to be particularly harmful, because habituation to the
opioid may occur with a gradual increase in opioid-
acetaminophen combination dosing over days or
A single dose of 10–15 g, occasionally less, may
produce clinical evidence of liver injury.
Fatal fulminant disease is usually (although not
Minimum toxic doses for single ingestion
Adults – 7.5-10 g
Children – 150mg/kg:200mg/kg in healthy
children aged 1-6 years.
Fatal dose : 20-25 g
Fatal period : 2 to 4 days
Serum acetaminophen concentration
Liver function tests – ALT, AST, Bilirubin(Direct and
indirect), alkaline phosphatase
Prothromin time with International normalised ratio
Renal function tests(electrolytes, BUN, creatinine)
Lipase and amylase(c/o abdominal pain)
Arterial blood gas analysis and ammonia
Urinanalysis( for hematuria and proteinuria)
ECG(to detect additional clues for co-ingestants)
CT brain(if altered mental status)
Blood levels of acetaminophen correlate with
severityof hepatic injury (levels >300 μg/mL 4 h
after ingestion are predictive of the development
of severe damage; levels <150 μg/mL suggest
that hepatic injury is highly unlikely).
Whether or not a clear history of overdose can be
elicited, clinical suspicion of acetaminophen
hepatotoxicity should be raised by the presence
of the extremely high aminotransferase levels in
association with low bilirubin levels that are
characteristic of this hyperacute injury
FACTORS THAT ALTER RISK
Induced P450 : chronic alcohol,
barbiturates, phenobarbital, isoniazid,
Glutathione depletion: chronic
ingestion paracetamol, malnutrition,
Hepatitis C virus(HCV) infection was
found to be associated with an
increased risk of acute liver injury in
patients hospitalized for acetaminophen
Therefore, in chronic alcoholics, the
toxic dose of acetaminophen may be as
low as 2 g, and alcoholic patients should
be warned specifically about the
dangers of even standard doses of this
commonly used drug.
As there are no early symptoms that predict
acetaminophen toxicity, poisoning severity
following an acute ingestion is quantified by
plotting a timed serum acetaminophen
concentration on the modified Rumack-Matthew
nomogram, drawn no less than 4 hours after
ingestion, serves as a guide for management.
Rumack-Matthew nomogram (the acetaminophen
toxicity nomogram or acetaminophen nomogram), is
used to interpret serum acetaminophen
concentrations in relation to time since ingestion, in
order to assess potential hepatotoxicity.
The nomogram predicts the risk of hepatotoxicity on
a single acetaminophen concentraion, measured at
one time. It is not a prognostic tool and, hence, does
not predict fulminant hepatic failure or death.
The nomogram predicts potential toxicity beginning at
4 hours after ingestion up to 24 hours after ingestion.
Acetaminophen concentraions measured earlier than
4 hours post-ingestion may not be reliable.
Concentrations measured 4-18 hours post-ingestion
The upper line of the nomogram is the “probable”
line, also known as the Rumack-Matthew line. About
60% of patients with values above this line develop
hepatotoxicity. The lower line on the nomogram is the
“possible” line, which was subsequently added later
per request of the U.S. FDA. The possible line, also
known as the “treatment” line, incorporates a 25%
margin of error in measurement variations or
uncertainty regarding the time of ingestion.
The nomogram cannot be used if the patient
presents more than 24 hours after ingestion or has a
history of multiple acetaminophen ingestions. Its
reliability decreases for ingestions of extended-
release acetaminophen formulations or for co-
ingestions of acetaminophen with agents that delay
gastric emptying and acetaminophen absorption
(e.g.anticholinergics or opioids).
Treatment includes gastric lavage, supportive
measures, and oral administration of activated
charcoal or cholestyramine to prevent absorption of
Treatment with activated charcoal (AC), 1 g/kg
(maximum dose 50 g) by mouth in all patients who
present within four hours of a known or suspected
acetaminophen ingestion, unless there are
contraindications to its administration like sedated
patients not on endotracheal tube and those
presenting after 4 hours of overdose.
Studies have shown that induced emesis and gastric
lavage limit the absorption of acetaminophen after
simulated overdose and in clinical trials However,
these therapies appear to be less effective than
activated charcoal, so they are not routinely
N-acetylcysteine is the accepted antidote for
acetaminophen poisoning and is given to all patients
at significant risk for hepatotoxicity. Serious
hepatotoxicity is uncommon and death extremely rare
if N-acetylcysteine is administered within eight hours
following acetaminophen overdose.
The key to effective treatment is to start therapy
before the onset of liver injury, which can be defined
biochemically by an elevation of the alanine
In patients with high acetaminophen blood levels
(>200 μg/mL measured at 4 h or >100 μg/mL at 8 h
after ingestion), the administration of N-acetylcysteine
In addition, when N-acetylcysteine is
administered late following acetaminophen
ingestion to patients with evidence of hepatic
failure, it decreases mortality and improves
hepatic and cerebral function
This agent provides sulfhydryl donor groups to
replete glutathione,which is required to render
harmless toxic metabolites that would otherwise
bind covalently via sulfhydryl linkages to cell
proteins,resulting in the formation of drug
Indications for N-acetylcysteine
Serum acetaminophen concentration drawn at four hours
or more following acute ingestion of an immediate-release
preparation is above the "treatment" line of the treatment
nomogram for acetaminophen poisoning
A suspected single ingestion of greater than 150 mg/kg
(7.5 g total dose regardless of weight) in a patient for
whom the serum acetaminophen concentration will not be
available until more than eight hours from the time of the
Patient with an unknown time of ingestion and a serum
acetaminophen concentration >10 mcg/mL (66 µmol/L).
Patient with a history of ingestion and evidence of ANY
Patients with delayed presentation (>24 hours after
ingestion) consisting of laboratory evidence of liver injury
(ranging from mildly elevated aminotransferases to
20 hour IV protocol — The 20 hour intravenous
(IV) protocol for N-acetylcysteine treatment has
been used in the United Kingdom since the
The approved 20 hour IV dosing regime is
complicated and is performed as follows:
150 mg/kg in 200 mL of D5W infused over 1 hour,
followed by 50 mg/kg in 500 mL of D5 W over 4
hours and then 100 mg/kg in 1000 mL of D5W
over 16 hours
This treatment protocol provides a total of 300
mg/kg over 20 to 21 hours
72 hour oral protocol — The 72 hour oral (PO) dosing
protocol for N-acetylcysteine treatment has been used
successfully in the United States for more than 30
years, and consists of the following:
A loading dose of 140 mg/kg PO, followed by
A dose of 70 mg/kg PO every four hours for a total of
The dose does not need to be adjusted if the patient
has been treated with activated charcoal.
The incidence of hepatotoxicity for patients treated
within eight hours of ingestion is less than 10 percent,
but increases to approximately 40 percent if treatment
is delayed beyond 16 hours.
A 12-hour protocol for N-acetylcysteine treatment -
involves the administration of 100 mg/kg of N-
acetylcysteine over two hours as a loading dose, and then
administration of 200 mg/kg over 10 hours
Intermittent IV infusion may be considered for late-
presenting or chronic ingestion. A loading dose of 140
mg/kg IV (diluted in 500 mL D5W) is infused over 1 h.
Maintenance doses of 70 mg/kg IV are given every 4 hours
for at least 12 doses (dilute each dose in 250 mL of D5W
and infuse over a minimum of 1 hour).
— Current dosing protocols for N-acetylcysteine in the
United States are calculated using patient bodyweight.
However, the maximum dose is based upon a weight of
100 kg for IV therapy and 110 kg for oral therapy
Clinicians often based dosing on actual weight with a low
rate of adverse events .
In most patients, either the oral or IV route is
acceptable. IV administration is favored for
patients with any of the following:
Contraindications to oral administration
(ie,pancreatitis,bowel ileus or obstruction, bowel
Patients who refuse oral administration
Patients with evidence of hepatic failure
NAC adverse effects
‘Non-IgE mediated anaphylaxis (previously called
anaphylactoid reactions) with intravenous
administration and vomiting with oral administration
are the most common adverse reactions associated
with N-acetylcysteine administration.
Like urticaria, flushing, angio oedema, wheezing ,
Patients receiving IV N-acetylcysteine warrant close
monitoring and all essential medications and tools
needed to treat anaphylaxis and airway emergencies
should be immediately available. These include
oxygen, antihistamine medication (eg,
diphenhydramine and ranitidine), albuterol,
epinephrine (1:1000 for intramuscular use),
with oral N-acetylcysteine develop nausea and
vomiting. Serotonin 5-HT3 receptor antagonists
(eg, ondansetron) are useful antiemetics. If the
patient vomits within 60 minutes of an oral dose
of N-acetylcysteine, the dose of N-acetylcysteine
should be repeated.
An alternative antidote is methionine 2.5 g orally
(adult dose) every 4 hours to a total of 4 doses
upto a total of 10 grams orally, but this is less
effective, especially after delayed presentation.
Do not give activated charcoal as it will bind
It acts by increasing glutathione synthesis.
If patient presents 8-24 hours or later after an
acute ingestion, initiate therapy immediately and
evaluate for laboratory evidence of hepatatoxicity.
NAC administration in such cases has decreased
incidence of cerebral oedema and improved
Proposed mechanism in this setting include an
antioxidant effect, decreased neutrophil
accumulation and improved microcirculatory
blood flow supporting increased oxygen delivery
to hepatic tissue.
If a patient presents after multiple ingestions or
chronic ingestion of supratherapeutic doses of
acetaminophen over hours or days, evaluate for
the presence of a persistent serum APAP
concentration and laboratory indicators of
hepatotoxicity. Begin NAC therapy if the patient
has elevated aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) levels or a
measurable serum APAP concentration.
Extended-release acetaminophen consists of
acetaminophen 325 mg in immediate release (IR)
form surrounding a matrix of acetaminophen 325
mg formulated for slow release. Some alteration
of the elimination kinetics of this preparation may
affect the reliability of the Rumack-Matthew
nomogram to predict potential hepatotoxicity and
subsequent treatment based on serum APAP
Several studies show that the elimination of ER
and IR APAP preparations is nearly identical after
4 hours. However, some case reports have
documented APAP levels that are above the
Given these findings, recommended
management for overdose of ER preparations
includes the measurement of 4-, 6-, and 8-hour
APAP concentrations. Begin NAC therapy if any
level crosses above the nomogram treatment
line. If the 6-hour level is greater than the 4-hour
level, begin NAC therapy.
More prolonged monitoring of APAP levels may
be necessary if the patient has food in his or her
stomach or has taken co-ingestants that delay
If signs of hepatic failure (e.g., progressive jaundice,
coagulopathy, confusion) occur despite N-
acetylcysteine therapy for acetaminophen
hepatotoxicity, liver transplantation may be the only
The United Kingdom King's College Hospital criteria
for the determination of the urgent need for
transplantation after acetaminophen-induced
fulminant hepatic failure include any one of the
Arterial pH less than 7.3 after fluid
resuscitation(lactate levels >3.5 mmol/L)
Grade III or IV encephalopathy
Prothrombin time (PT) greater than 100 seconds
Serum creatinine level greater than 3.4 mg/dL
Because of the limited safety margin between
safe and toxic doses, the FDA has recommended
that the daily dose of acetaminophen be reduced
from 4 g to 3 g (even lower for persons with
chronic alcohol use), that all acetaminophen-
containing products be labeled prominently as
containing acetaminophen, and that the potential
for liver injury be prominent in the packaging of
acetaminophen and acetaminophen-containing
Within opioid combination products, the limit for
the acetaminophen component has been lowered
to 325 mg per tablet
The essential of forensic medicine and toxicology
by K. Narayan reddy
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