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CLINICAL TOXICOLOGY
I. PARACETAMOLBACKGROUNDParacetamol is also known as
acetaminophen. It is widely used as an analgesic and antipyretic.
It is generally considered as a safe drug though it still can cause
death through overdose, idiopathic reaction, or synergism with
alcoholic liver disease.Paracetamol is available as: tablets
caplets capsules soluble tablets (these dissolve in water, which
you then drink) an oral suspension (liquid medicine) suppositories,
which are inserted into your anus (the opening through which waste
leaves your body)AbsorptionIt is wellabsorbedin the
gastrointestinal tract, stomach and small intestine.
Oralbioavailabilityis dose dependent: with larger doses
bioavailability is increased due to the reduced first pass effect.
Rectal administration of paracetamol has 30-70% bioavailability. In
this case, bioavailability is overall reduced, due to incomplete
dissolution of the suppository in the rectum.
DistributionParacetamol isdistributedthroughout the body. The
analgesic activity can be attributed to the small fraction that
penetrates into the brain. Paracetamol given at therapeutic doses
binds toplasma proteinsat less than 20%. In case of intoxication,
this proportion may increase to up to 50%.
Metabolism Paracetamol is essentiallymetabolizedin the liver by
conjugation to non-toxic water-soluble compounds. Hepatotoxic
metabolites are produced in small amounts by the cytochrome P450
(isoenzyme CYP2E1). In the therapeutic plasma concentration range,
this metabolite is detoxified by conjugation with glutathione. In
case of intoxication the amount of this toxic metabolite increases
and outweighs the amount of available glutathione, which can lead
to hepatic failure and renal tubular necrosis. When the maximum
daily dose is exceeded over a prolonged period of time, the
hepatotoxic reactive metabolite N-acetyl-p-benzoquinoneimine
(NAPQI) is produced.
Excretion Metabolites areexcretedthrough the kidneys in the
urine. Only 2-5% of the dose is excreted in an unchanged form in
the urine. As a consequence of its short
eliminationhalf-life(1-3h), 24 hours after the ingestion of a
single dose of paracetamol, 98% of the dose is eliminated.
Clinical implications Since paracetamol is mostly eliminated by
hepaticmetabolism, patients with severe hepatic failure have a
considerably longer eliminationhalf-life, and therefore,
paracetamol must be used cautiously in such patients.
EpidemiologyParacetamol toxicity is the most common cause of
hepatic failure requiring liver transplantation in Great Britain.
In the United States, paracetamol toxicity has replaced viral
hepatitis as the most common cause of acute hepatic failure and is
the second most common cause of liver failure requiring
transplantation. Although acetaminophen toxicity is particularly
common in children, adults have accounted for most of the serious
and fatal cases.
II. CHEMISTRYChemical structure
pKa = 9.46solubility = 4.15partition coefficient = log P
0.31
III. MECHANISM OF TOXICITYOrgan SystemAcetaminophen overdose is
associated liver failure, which is caused by massive hepatic
necrosis, the distinct feature of acetaminophen toxicity. In
addition to liver, however, many organ systems may fail under acute
overdose such as renal, cardiac, and central nervous systems. It is
thought that the liver is the target organ for acetaminophen
toxicity because this is primarily where the drug is detoxified.
Under normal conditions, acetaminophen is mainly metabolized by
undergoing sulfation and glucuronidation. It has been proposed that
a small amount of drug goes through the cytochrome P450 mixed
function oxidase system and is metabolized into the reactive
intermediateN-acetyl-P-benzoquinoneimine (NAPQI), which is in turn
detoxified by reaction with glutathione. When large quantities of
acetaminophen are consumed, the three detoxification pathways
become saturated.
CellularThe precise mechanism by which acetaminophen causes cell
death remains unknown, although there are two theories possible.
The first theory, the oxidative stress theory, maintains that
acetaminophen metabolites cause oxidative stress in the cell
ultimately leading to its demise. The depletion of cellular
glutathione, a natural antioxidant, leaves the cell particularly
vulnerable to oxidative insults following acetaminophen
overdose.The second theory, the covalent binding theory, states
that the binding of the highly reactive acetaminophen metabolites
to cell macromolecules causes cell deathIV.
TOXICOKINETICSABSORPTION:Paracetamol is normally rapidly absorbed
and peak concentrations occur within 1-2 hours for standard tablet
or capsules and even quicker (< 0.5 h) in liquid preparations.
There are two sustained release preparations and absorption from
these continues for up to 12 hours in therapeutic doses and much
longer in overdose. Prolonged absorption is seen following large
ingestions( > 500 mg/kg) and with coingestion of drugs that slow
gastrointestinal motility ( opiates & anticholinergic)
DISTRIBUTION:After absorption, paracetamol distributes rapidly
with a volume of distribution of 0.9 L/kg.Absorption and
distribution are completed by 4 hours post overdose with standard
release preparations and within 2 hours in liquid preparations.
PROTEIN BINDING: 25%
Paracetamol is metabolised by a number of pathways. The majority
of metabolism is by glucuronidation and sulphation. There is some
first pass metabolism (about 20%) due to sulfation in the gut wall.
The half-life of paracetamol in therapeutic use is 1.5 to 3 hours.
The half-life may become prolonged in overdose to greater than 4
hours. A prolonged half-life has been linked to a higher risk of
toxicity, which may indicate this is due to saturation of
conjugation pathways and an increasing proportion of paracetamol
being metabolised by P450 enzymes.
The minor pathways involving P450 enzymes account only for about
5-10% of paracetamol metabolism in therapeutic use. These lead to
production of a toxic metabolite, N-acetyl-p-benzoquinonimine
(NAPQI). This conjugates with glutathione and is excreted as a
non-toxic conjugate in the urine. As glutathione is depleted, this
reactive metabolite binds covalently to hepatic macromolecules
leading to cell dysfunction death and apoptosis.
EXCRETION Approximately 80% of acetaminophen is excreted in the
urine after conjugation and about 3% is excreted unchanged.
V. CLINICAL TOXICOLOGYEvidence of end-organ toxicity often does
not manifest until 24-48 hours after an acute ingestion. To
identify whether a patient is at risk, the clinician should
determine the time(s) of ingestion, the quantity, and the
formulation of acetaminophen ingested.Minimum toxic doses of
acetaminophen for a single ingestion, posing significant risk of
severe hepatotoxicity, are as follows:Adults: 7.5-10 gChildren: 150
mg/kg; 200 mg/kg in healthy children aged 1-6 years The clinical
course of acetaminophen toxicity generally is divided into four
phases. Physical findings vary, depending primarily on the level of
hepatotoxicity.Phase 1 0.5-24 hours after ingestion Patients may be
asymptomatic or report anorexia, nausea or vomiting, and malaise
Physical examination may reveal pallor, diaphoresis, malaise, and
fatigue
Phase 2 18-72 h after ingestion Patients generally develop right
upper quadrant abdominal pain, anorexia, nausea, and vomiting Right
upper quadrant tenderness may be present Tachycardia and
hypotension indicate ongoing volume losses Some patients may report
decreased urinary output (oliguria)
Phase 3: Hepatic phase 72-96 h after ingestion Patients may have
continued nausea and vomiting, abdominal pain, and a tender hepatic
edge Hepatic necrosis and dysfunction are associated with jaundice,
coagulopathy, hypoglycemia, and hepatic encephalopathy Acute renal
failure develops in some critically ill patients Death from multi
organ failure may occur
Phase 4: Recovery phase 4 days to 3 weeks after ingestion
Patients who survive critical illness in phase 3 have complete
resolution of symptoms and complete resolution of organ failure
First Aid and Management
Gastrointestinal decontamination agents can be used in the
emergency department setting in the immediate post-ingestion time
frame. Administer activated charcoal (AC) if the patient is alert
and presents, ideally, within 1 hour post ingestion. This time
frame can be extended if the patient ingested an
acetaminophen-based sustained-release medication or if the
ingestion includes agents that are known to slow gastric emptying.
Patients with acetaminophen levels below the possible" line for
hepatotoxicity on the Rumack-Matthew nomogram may be discharged
home after they are medically cleared.Admit patients with
acetaminophen plasma levels above the possible line on the
Rumack-Matthew nomogram for treatment withN-acetylcysteine (NAC).
NAC is nearly 100% hepatoprotective when it is given within 8 hours
after acute acetaminophen ingestion, but can be beneficial in
patients who present more than 24 hours after ingestion. NAC is
approved for both oral and IV administration.The FDA-approved
regimen for oral administration of NAC is as follows: Loading dose
of 140 mg/kg 17 doses of 70 mg/kg given every 4 hours Total
treatment duration of 72 hours The IV formulation of NAC
(Acetadote) is commonly used in many institutions for the treatment
of acetaminophen ingestion. Use of the IV formulation of NAC is
preferred in the following situations: Altered mental status GI
bleeding and/or obstruction A history of caustic ingestion
Potential fetal acetaminophen toxicity in a pregnant woman
Inability to tolerate oral NAC because of emesis refractory to
proper use of antiemetics.
Surgical evaluation for possible liver transplantation is
indicated for patients who have severe hepatotoxicity and potential
to progress to hepatic failure. Criteria for liver transplantation
include the following: Metabolic acidosis Renal failure
Coagulopathy Encephalopathy
Signs & Symptoms:Patients may complain of anorexia, nausea,
vomiting, and hepatic tenderness.They may develop any of the
following complications:Hypoglycaemiahepatic
encephalopathyjaundicecoagulopathyFIRST AID of PoisoningFor small
amounts, you may be told to watch the person carefully at home.
For a larger amount, you may need to take the person to a
hospital emergency department.In high doses, acetaminophen can
cause damage to the liver. At the hospital, doctors will check the
level of acetaminophen in the blood and may give activated charcoal
or antidote medication to prevent the toxic effect on the body.
MECHANICAL ANTIDOTAL MEASURES Emptying of the stomach:In the
very few cases in which a person comes to the hospital minutes
after taking the overdose, the doctor may attempt to empty the
stomach. This can be accomplished by inducing vomiting or by
placing a large tube through the person's mouth and into the
stomach, putting fluid in and then pumping it out (gastric lavage).
Activated charcoal:Activated charcoalcan be given by mouth to bind
any drug remaining in the gastrointestinal tract.
Algorithm of Treatment
Initial appropriate supportive care is essential in
acetaminophen poisoning. Immediate assessment of the patient's
airway, breathing, and fluid status (ie, ABCs) is critical before
treatment for suspected acetaminophen overdose is initiated. In
addition, assessing for other potential life-threatening
co-ingestions (eg, salicylate) is very important.Administer
activated charcoal (AC) if the patient has a stable mental and
clinical status and presents to the emergency department within 1
hour of ingestion. Draw a 4-hour serum acetaminophen concentration
to determine the risk for hepatotoxicity, plot this value using the
Rumack-Matthew nomogram.Patients with acetaminophen levels below
the possible line for hepatotoxicity on the Rumack-Matthew nomogram
may be discharged home after they are medically cleared. If the
ingestion occurred with intent to do self-harm, a thorough
psychosocial, psychological and/or psychiatric evaluation is
indicated before the patient can be discharged safely from the
medical care facility.Admit patients with acetaminophen plasma
levels above the possible line on the Rumack-Matthew nomogram for
treatment withN-acetylcysteine (NAC). Treat patients with evidence
of hepatic failure, metabolic acidosis, coagulopathy, and/or
encephalopathy in an intensive care unit (ICU). Transfer patients
with evidence of clinically significant hepatotoxicity to a medical
facility with
intensive care support and organ transplant services.More
important than GI decontamination after APAP ingestion is the early
administration of NAC.NAC is nearly 100% hepatoprotective when it
is given within 8 hours after an acute acetaminophen ingestion.
Guidelines from the American College of Emergency Physicians
recommend the use of NAC to treat acute acetaminophen overdose in
patients with either possible or probable risk for hepatotoxicity,
according to the Rumack-Matthew nomogram, ideally within 8-10 hours
post ingestion. Because of the benign nature of NAC, and the risk
of adverse effects from acetaminophen toxicity, NAC should be given
even if the history is unclear but a potentially toxic
acetaminophen ingestion is suspected. NAC should be administered
while awaiting a serum APAP level if the patient presents close to
or later than 8 hours after an acute ingestion, or if the patient
is pregnant.A late presentation should not preclude NAC
administration if the history or presentation suggests potential
toxicity.Failure to administer NAC because of late presentation is
considered medically and legally inappropriate.Surgical evaluation
for possible liver transplantation is indicated for patients who
have severe hepatotoxicity and potential to progress to hepatic
failure. Criteria for liver transplantation include the following:
Metabolic acidosis Renal failure Coagulopathy Encephalopathy
Diagnosis
AST, ALT, and serum acetaminophen levelsThe Rumack-Matthew
nomogram cannot be used, but likelihood of clinically significant
hepatotoxicity can be estimated based on AST, ALT, and serum
acetaminophen levels. If AST and ALT levels are normal (
