Acetaminophen overdose

Researcher: Mehrasa Nikandish
Subject: toxicology
 Introduction
 Acute acetaminophen poisoning
 Chronic acetaminophen poisoning
 Diagnosis
 Treatment
 Management of paracetamol overdose
 Hepatoxicity
 Non- hepatic toxicity
 Pancreatic toxicity
 Acetaminophen is a nonsteroidal anti –
inflammatory drug with potent antipyretic and
analgesic actions but with very weak anti-
inflammatory activity.
 Acetaminophen is an analgesic used to temporarily relieve
minor aches and pains due to headache, muscular aches,
backache, minor pain of arthritis, the common cold,
toothache, and premenstrual and menstrual cramps.
 Acetaminophen is also used to temporarily reduce fever.
 In general, acetaminophen is well-tolerated when
administered in therapeutic doses. The most commonly
reported adverse reactions have included nausea,
vomiting, constipation. Injection site pain and injection site
reaction have been reported with the IV product.
 Acetaminophen poisoning can
cause gastroenteritis within
hours and hepatotoxicity 1 to 3
days after ingestion. Severity of
hepatotoxicity after a single
acute overdose is predicted by
serum acetaminophen levels.
Treatment is with N-
acetylcysteine to prevent or
minimize hepatotoxicity.
 To cause toxicity, an acute oral
overdose must total ≥ 150 mg/kg
(about 7.5 g in adults) within 24
hours.
 IV acetaminophen: An IV
formulation of acetaminophen that
is designed for use in hospitals and
in patients > 2 years of age has
been associated with several
hundred reports of overdoses,
including several dozen fatalities,
several in children.
 Chronic excessive use or repeated
overdoses cause hepatotoxicity in a
few patients. Usually, chronic
overdose is not an attempt at self-
injury but instead results from
taking inappropriately high doses
to treat pain. Symptoms may be
absent or may include any of those
symptoms that occur with acute
overdose.
Acute acetaminophen
poisoning
 Serum acetaminophen levels - Rumack-Matthew
nomogram.
 Acetaminophen overdose should be considered in
all patients with nonaccidental ingestions that may
be suicide attempts and in children with ingestions
because formulations
containing acetaminophen are frequently ingested
in such overdoses and are not reported. Also,
because acetaminophen often causes minimal
symptoms during the early stages and is potentially
lethal but treatable, ingestion should be considered
in all patients with accidental ingestions as well.
Likelihood and severity of hepatotoxicity caused by
an acute ingestion can be predicted by the amount
ingested or, more accurately, by the
serum acetaminophen level.
Chronic Acetaminophen
Poisoning
 Aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and serum acetaminophen
levels. The 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 (< 50 IU/L [0.83
microkat/L]), and the acetaminophen level is < 10 mcg/mL
(< 66 micromol/L), significant hepatotoxicity is very unlikely.
 If AST and ALT levels are normal but the acetaminophen
level is ≥ 10 mcg/mL (> 66 micromol/L), significant
hepatotoxicity is possible; AST and ALT levels are
remeasured after 24 hours.
 If repeat AST and ALT levels are normal, significant
hepatotoxicity is unlikely; if the levels are high,
significant hepatotoxicity is assumed.
 If initial AST and ALT levels are high, regardless of the
acetaminophen level, significant hepatotoxicity is
assumed.
Acute acetaminophen
poisoning
 Oral or IV N-acetylcysteine
 Possibly activated charcoal
 Activated charcoal may be given
if acetaminophen is likely to still remain in the
gastrointestinal (GI) tract. N-Acetylcysteine is an
antidote for acetaminophen poisoning.
 This drug is a glutathione precursor that
decreases acetaminophen toxicity by increasing
hepatic glutathione stores and possibly via other
mechanisms. It helps prevent hepatic toxicity by
inactivating the toxic acetaminophen metabolite
NAPQI (N-acetyl-p-benzoquinone imine) before
it can injure liver cells.
Chronic Acetaminophen
Poisoning
 Sometimes N-acetylcysteine. The role of N-acetylcysteine in
treatment of chronic acetaminophen toxicity or in the
presence of established acute hepatotoxicity is unclear.
Theoretically, the antidote may have some benefit if given >
24 hours after an ingestion if residual (unmetabolized)
acetaminophen is present.
 If hepatotoxicity is possible (if aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) levels are normal
and acetaminophen level is initially elevated), N-
acetylcysteine is given 140 mg/kg orally loading dose and
70 mg/kg orally every 4 hours for the first 24 hours.
 If repeat AST and ALT levels (after 24 hours) are normal, N-
acetylcysteine is stopped; if repeat levels are high, they are
remeasured daily, and N-acetylcysteine is continued until
levels are normal.
 If hepatotoxicity is likely (especially if initial AST and ALT
levels are high), a full course of N-acetylcysteine is given.
Management of the Paracetamol Overdose
Gastrointestinal
decontamination
• The administration of
activated charcoal within 4
hours of the paracetamol
ingestion reduces its further
absorption and the further
need for N acetyl cysteine
administration. The usual
dose of activated charcoal in
adults is 25-50 gm in 100-
200 ml of water (0.5 -1
gm/kg body weight).
Antidotes
• Since it is the relative
scarcity of the SH groups
that leads to the
hepatotoxicity which is
caused by paracetamol, the
definitive therapy has been
directed towards the
measures which are taken to
restore it. The first of such
agents were cysteine and
methionine, which provided
encouraging results by
replenishing the lost
glutathione stores.
N-Acetylcysteine
• Acetylcysteine (also known
as N-acetylcysteine)
prevents the hepatic injury,
primarily by restoring hepatic
glutathione. It is thought to
provide cysteine for the
glutathione synthesis and
possibly to form an adduct
directly with the toxic
metabolite of acetaminophen
and N-acetyl-p-
benzoquinoneimine and to
thus prevent its covalent
bonding to the hepatic
proteins.
 Most hepatotoxicity probably results from a toxic
intermediary products causing hepatic necrosis.
 Alternate explanations of necrosis involve:
1. Lipid peroxidation
2. Oxidation of thiol groups
 The liver metabolized most therapeutic doses of
acetaminophen by glucuronide and sulfate conjugation.
Only small amounts of acetaminophen are converted to
the highly reactive intermediate N-acetyl-p-
benzoquinoneimine (NAPQI) by the cytochrome P450
mixed – function oxidase system.
 gluthatione rapidly detoxifies this intermediate to
cysteine and mercapturate conjugates.
One explanation of acetaminophen
hepatotoxicity is the saturation of the
sulfate pathway by the ingestion of an
excessive acetaminophen dose.
Risk factors include alcoholism and
chronic ingestion of agents that induce
hepatic microsomal enzymes; e.g.
isoniazid.
Starvation depletes glutathione stores.
Toxic dose in adults:
5 – 15 mg [15-45 tablets of 325 mg
each]
Lethal dose:
13 – 25 mg [46-75 mg of 325 mg each]
 Renal failure:
 The kidney also metabolizes
acetaminophen to a toxic
intermediate, which binds to renal
macromolecules, leading to cell
death.
 Oliguric renal failure may become
apparent within 24 to 48 hours of
acetaminophen overdose.
Pancreatic toxicity
 Doses of acetaminophen as low as
9.75 g have been associated with
pancreatitis. Hyperamylasemia is
often observed.
 Cardiotoxicity: acetaminophen –
induced cardiotoxicity is rarely
clinically significant, but if ST/T –
wave abnormalities or a dysrhythmia
is present, treatment with N-
acetylcysteine should be considered,
probably irrespective of the plasma
acetaminophen level or time lapse
since ingestion.
Hypersensitivity
reactions
 Allergic reactions to acetaminophen are
rare and usually involve the skin.
 Bronchospasm and urticarial have been
reported in adults.
 Dose – dependent anaphylactoid
reactions.
Stage Time following
ingestion
Characteristics
I ½ - 24 hour Anorexia, nausea,
vomiting, malaise, pallor
II 24 – 48 hour Abd.pain, liver
tenderness, elevated
liver enzymes, oliguria
III 72 – 96 hour Peak hepatic enzymes,
abn. Bilirubin, PT
IV 4 days – 2 week Resolution or
progressive hep. failure
Acetaminophen overdose
1 sur 12

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Acetaminophen overdose

  • 2.  Introduction  Acute acetaminophen poisoning  Chronic acetaminophen poisoning  Diagnosis  Treatment  Management of paracetamol overdose  Hepatoxicity  Non- hepatic toxicity  Pancreatic toxicity
  • 3.  Acetaminophen is a nonsteroidal anti – inflammatory drug with potent antipyretic and analgesic actions but with very weak anti- inflammatory activity.  Acetaminophen is an analgesic used to temporarily relieve minor aches and pains due to headache, muscular aches, backache, minor pain of arthritis, the common cold, toothache, and premenstrual and menstrual cramps.  Acetaminophen is also used to temporarily reduce fever.  In general, acetaminophen is well-tolerated when administered in therapeutic doses. The most commonly reported adverse reactions have included nausea, vomiting, constipation. Injection site pain and injection site reaction have been reported with the IV product.  Acetaminophen poisoning can cause gastroenteritis within hours and hepatotoxicity 1 to 3 days after ingestion. Severity of hepatotoxicity after a single acute overdose is predicted by serum acetaminophen levels. Treatment is with N- acetylcysteine to prevent or minimize hepatotoxicity.
  • 4.  To cause toxicity, an acute oral overdose must total ≥ 150 mg/kg (about 7.5 g in adults) within 24 hours.  IV acetaminophen: An IV formulation of acetaminophen that is designed for use in hospitals and in patients > 2 years of age has been associated with several hundred reports of overdoses, including several dozen fatalities, several in children.  Chronic excessive use or repeated overdoses cause hepatotoxicity in a few patients. Usually, chronic overdose is not an attempt at self- injury but instead results from taking inappropriately high doses to treat pain. Symptoms may be absent or may include any of those symptoms that occur with acute overdose.
  • 5. Acute acetaminophen poisoning  Serum acetaminophen levels - Rumack-Matthew nomogram.  Acetaminophen overdose should be considered in all patients with nonaccidental ingestions that may be suicide attempts and in children with ingestions because formulations containing acetaminophen are frequently ingested in such overdoses and are not reported. Also, because acetaminophen often causes minimal symptoms during the early stages and is potentially lethal but treatable, ingestion should be considered in all patients with accidental ingestions as well. Likelihood and severity of hepatotoxicity caused by an acute ingestion can be predicted by the amount ingested or, more accurately, by the serum acetaminophen level. Chronic Acetaminophen Poisoning  Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum acetaminophen levels. The 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 (< 50 IU/L [0.83 microkat/L]), and the acetaminophen level is < 10 mcg/mL (< 66 micromol/L), significant hepatotoxicity is very unlikely.  If AST and ALT levels are normal but the acetaminophen level is ≥ 10 mcg/mL (> 66 micromol/L), significant hepatotoxicity is possible; AST and ALT levels are remeasured after 24 hours.  If repeat AST and ALT levels are normal, significant hepatotoxicity is unlikely; if the levels are high, significant hepatotoxicity is assumed.  If initial AST and ALT levels are high, regardless of the acetaminophen level, significant hepatotoxicity is assumed.
  • 6. Acute acetaminophen poisoning  Oral or IV N-acetylcysteine  Possibly activated charcoal  Activated charcoal may be given if acetaminophen is likely to still remain in the gastrointestinal (GI) tract. N-Acetylcysteine is an antidote for acetaminophen poisoning.  This drug is a glutathione precursor that decreases acetaminophen toxicity by increasing hepatic glutathione stores and possibly via other mechanisms. It helps prevent hepatic toxicity by inactivating the toxic acetaminophen metabolite NAPQI (N-acetyl-p-benzoquinone imine) before it can injure liver cells. Chronic Acetaminophen Poisoning  Sometimes N-acetylcysteine. The role of N-acetylcysteine in treatment of chronic acetaminophen toxicity or in the presence of established acute hepatotoxicity is unclear. Theoretically, the antidote may have some benefit if given > 24 hours after an ingestion if residual (unmetabolized) acetaminophen is present.  If hepatotoxicity is possible (if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are normal and acetaminophen level is initially elevated), N- acetylcysteine is given 140 mg/kg orally loading dose and 70 mg/kg orally every 4 hours for the first 24 hours.  If repeat AST and ALT levels (after 24 hours) are normal, N- acetylcysteine is stopped; if repeat levels are high, they are remeasured daily, and N-acetylcysteine is continued until levels are normal.  If hepatotoxicity is likely (especially if initial AST and ALT levels are high), a full course of N-acetylcysteine is given.
  • 7. Management of the Paracetamol Overdose Gastrointestinal decontamination • The administration of activated charcoal within 4 hours of the paracetamol ingestion reduces its further absorption and the further need for N acetyl cysteine administration. The usual dose of activated charcoal in adults is 25-50 gm in 100- 200 ml of water (0.5 -1 gm/kg body weight). Antidotes • Since it is the relative scarcity of the SH groups that leads to the hepatotoxicity which is caused by paracetamol, the definitive therapy has been directed towards the measures which are taken to restore it. The first of such agents were cysteine and methionine, which provided encouraging results by replenishing the lost glutathione stores. N-Acetylcysteine • Acetylcysteine (also known as N-acetylcysteine) prevents the hepatic injury, primarily by restoring hepatic glutathione. It is thought to provide cysteine for the glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen and N-acetyl-p- benzoquinoneimine and to thus prevent its covalent bonding to the hepatic proteins.
  • 8.  Most hepatotoxicity probably results from a toxic intermediary products causing hepatic necrosis.  Alternate explanations of necrosis involve: 1. Lipid peroxidation 2. Oxidation of thiol groups  The liver metabolized most therapeutic doses of acetaminophen by glucuronide and sulfate conjugation. Only small amounts of acetaminophen are converted to the highly reactive intermediate N-acetyl-p- benzoquinoneimine (NAPQI) by the cytochrome P450 mixed – function oxidase system.  gluthatione rapidly detoxifies this intermediate to cysteine and mercapturate conjugates. One explanation of acetaminophen hepatotoxicity is the saturation of the sulfate pathway by the ingestion of an excessive acetaminophen dose. Risk factors include alcoholism and chronic ingestion of agents that induce hepatic microsomal enzymes; e.g. isoniazid. Starvation depletes glutathione stores. Toxic dose in adults: 5 – 15 mg [15-45 tablets of 325 mg each] Lethal dose: 13 – 25 mg [46-75 mg of 325 mg each]
  • 9.  Renal failure:  The kidney also metabolizes acetaminophen to a toxic intermediate, which binds to renal macromolecules, leading to cell death.  Oliguric renal failure may become apparent within 24 to 48 hours of acetaminophen overdose.
  • 10. Pancreatic toxicity  Doses of acetaminophen as low as 9.75 g have been associated with pancreatitis. Hyperamylasemia is often observed.  Cardiotoxicity: acetaminophen – induced cardiotoxicity is rarely clinically significant, but if ST/T – wave abnormalities or a dysrhythmia is present, treatment with N- acetylcysteine should be considered, probably irrespective of the plasma acetaminophen level or time lapse since ingestion. Hypersensitivity reactions  Allergic reactions to acetaminophen are rare and usually involve the skin.  Bronchospasm and urticarial have been reported in adults.  Dose – dependent anaphylactoid reactions.
  • 11. Stage Time following ingestion Characteristics I ½ - 24 hour Anorexia, nausea, vomiting, malaise, pallor II 24 – 48 hour Abd.pain, liver tenderness, elevated liver enzymes, oliguria III 72 – 96 hour Peak hepatic enzymes, abn. Bilirubin, PT IV 4 days – 2 week Resolution or progressive hep. failure