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2.  Phase
1 drug metabolism - alters
the parent molecule
 Phase 2 - conjugate of the drug or
its metabolite with a more watersoluble moiety
 Phase 3 - energy-dependent
excretion
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3.  Oxidation,
reduction, and hydrolytic
reactions
 Products of phase metabolism can be
readily conjugated or excreted
without further modification
 Catalyzed by microsomal
cytochrome P450 or CYP
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4.  Great
differences in drug metabolism
 In many severe liver diseases decreased levels of total CYP and
reduced hepatic perfusion
 Decrease in the clearance of drugs
that are rapidly metabolized by the
liver
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5.  Conjugate
of the drug or its
metabolite with
› glucuronic acid
› inorganic sulfate
 Highly
water-soluble and
excreted in bile or urine
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6.  Involves
the ATP-binding cassette
(ABC) transport proteins
› cystic fibrosis transmembrane
conductance regulator (CFTR)
› canalicular and intestinal copper
transporters
› multidrug resistance-related proteins
(MRP)
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7. Hepatocytes
- activate
oxygen (toxic)
Liver has antioxidant
mechanisms
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8. Most
important
antioxidant in the liver
Liver
is the only site of
glutathione synthesis
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9.  Increases
synthesis of glutathione
 NADPH - essential cofactor that
requires ATP
 Relation between energy-generating
capacity of the liver and its ability to
withstand oxidative stress
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10. Mitochondria – ROS constantly formed as a
by-product of oxidative respiration
 Mitochondrial glutathione is maintained by
active uptake from the cytosol
 Chronic ethanol exposure alters this
transport system - predispose to drug
toxicity

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11. Paracetamols
Oral
pills
contraceptive
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12. Not
dose
related
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13.  Single
ingestion > 7 to 10 g (150
mg/kg body weight in children)
 Fatal cases usually involve doses of at
least 15 to 25 g
 In heavy drinkers, daily doses of 2 to 6
g have been associated with fatal
hepatotoxicity
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14. 2
to 4 hours
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15. Phase
2 reaction
› Conjugation with sulfate
and glucuronide to form
nontoxic metabolites in
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16. Phase
1 reaction
› Oxidized by hepatic
cytochrome P450 enzymes
› Form n-acetyl-pbenzoquinoneimine (NAPQI)
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17.  Toxic
 Detoxified
by conjugation with
glutathione
 Mercapturic acid
› harmless and water-soluble
› renal excretion
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18.  NAPQI
produce liver injury
 Hepatic necrosis occurs only
when concentrations of
reduced glutathione fall below
a critical level
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19. Stimulates
hepatic
synthesis of reduced
glutathione
Protects the liver
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20.  Sulfate
and glucuronide pathways
saturated
 Increased amount of paracetamol
gets metabolized to NAPQI
 Glutathione levels depleted
 Free NAPQI - centrilobular necrosis
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21. Induces
cytochrome P450
Chronic alcoholics - toxic
dose of paracetamol may
be as low as two grams
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22. Decreases
glutathione
reserves
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23.  Nonspecific
› Nausea and vomiting
› Diarrhea
› Abdominal pain
› Shock
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24.  After
48 to 72 hours
› ALT - often between 2000 and
10,000 U/L
› Right upper quadrant
tenderness
› Jaundice
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25. Maximal
hepatic failure
may not be evident until 6
days after ingestion
Hepatic failure
Renal failure
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26.  Time
of presentation – cysteine
within 12 hours abolishes
significant liver injury
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27. Age
– Children relatively
resistant
Alcohol
and fasting
› Enhance activity of CYP
› Deplete hepatic glutathione
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28.  Grade
IV hepatic coma
 Acidosis - pH less than 7.30
 PT - Twofold prolongation
 Renal failure - Serum creatinine > 3.3
 Falling ALT with worsening PT
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29. Risk
of liver
injury
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30.  Between
4 and 24 h after ingestion reliable indicator
 Determine acetaminophen blood
levels at the time of presentation
 Blood levels within 4 hours of ingestion
may not be a reliable estimate delayed gastric emptying
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31. Antidote
of choice
Slow bolus IV injection
followed by infusion
Oral
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32.  Most
effective if started within
8 to 10 h of an overdose
 Discontinue - If the level is
subsequently shown to be
nontoxic
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33. Predictive
of severe
damage
< 150 ug/mL - hepatic injury
highly unlikely
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34.  Nausea,
vomiting, and epigastric
discomfort

Rash
 Angioedema
 Fatal
shock
 Close supervision and only for
appropriate indications
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35. In
patients known to be
sensitized to NAC,
methionine is probably
just as effective
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36. <
4 hours - empty the stomach
 Activated charcoal if < 4 h of
› does not interfere significantly
with acetylcysteine therapy
 Osmotic
cathartics –not
indicated
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37.  Paracetamol
poisoning - NAC
 Amanita - Penicillin G and NAC
 HSV – Acyclovir
 AIH - Methylprednisolone
 HBV - Lamivudine
 AFLP/HELLP - Delivery of fetus
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38. 
Reduce the toxin load
› Gastric lavage
› Instillation of charcoal
Hemodialysis - remove toxins from the
serum
 Lower entero-hepatic toxin load Uncertain

› pencillin, cytochrome c, and silymarin
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39. Life-saving
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