Clinical Toxicology Course

Acetaminophen Toxicity

Mohammed El-Sakkar, MD, PhD (Pharmacology), MSc (Pediatrics), Professor

Pharmacology Department
College of Clinical Pharmacy, IAU
2022
ILOs: By the end of this lecture the students Abbreviations:
must be able to APAP N-acetyl-para-aminophenol
§ Describe Mechanism of toxicity ATN acute tubular necrosis
§ Discuss Risk factors for acetaminophen BW Body Weight
toxicity GSH glutathione
§ Discuss Clinical features q every
§ Discuss significance of Investigations HE hepatic encephalopathy
ALF Acute liver failure
§ Discuss acetaminophen antidotes
AIALI, Acetaminophen (APAP)-induced acute liver injury
§ Discuss acetaminophen toxicity in Children glc glucose
§ Discuss acetaminophen toxicity in Pregnancy OD 'Once in a day'.
§ Discuss Staggered overdoses
§ Discuss Outcome of Tx of acetaminophen
overdose
§ Discuss the need of Liver transplantation in
acetaminophen toxicity
§ Discuss management of acetaminophen
poisoning
 time
single
↑
staggeredAcute Paracetamol Overdose
- '
Definitions
, s
§ Single time point overdose: overdose (>4 g) of paracetamol (‘acetaminophen’ in USA)
taken at single defined time point Therapatic
--
dase
- Si A
M

§ Staggered overdose: ingestion of ≥ 2 supratherapeutic acetaminophen doses over >8 h

due to self-medication for acute pain in adults or therapeutic error in children, resulting in
- -

3:2
o A cumulative dose of >4 g/day in adults or
->
65

o >60 mg/kg/d in children.

jas:Sess
re

=>
-

§ Delayed presentation: is presentation >24 h following the last ingestion of paracetamol.

> - -
-
> -

-
 -35 S s s
nt lic Mechanism of toxicity
- - 9
a
s o
ul coh
i
doses
not
Artic v
on c a
l
overdose
tuxic 5355 c
ti ni
n
A hro
can notetastied + C - NAPQI

"I
be

① Acetaminichen CYP 2E1 agent

Urinary
Excretion
paracetamo
APAP
E
=>

NAPQI
Toxic
s
Hepatocellular necrosis
2% 5-9%
-

A
② GSH

"I
Chr alcoholics

Reductase
GSH- Anorexia, cachexia
90% dependent - Malnutrition
Glucuronidation
pathway Liver dis
Sulfation Sis Advanced
- age
GSSG
~Apat3.-08
b
(Glutathione disulfide)

Glucuronide and sulfate S Cysteine conjugate and

-

metabolites (non-toxic) mercapturic acid (non-toxic)

-
excreted

NAPQI; N-acetyl-p-benzoquinoneimine
 Mechanism of toxicity
§ A metabolite of acetaminophen (N-acetyl-p-benzoquinone imine, NAPQI) neutralized by
GSH in liver. When stores of GSH exhausted (30% of normal) by paracetamol overdose,
S
-

NAPQI starts binding to other proteins Ò

-

o Early: mitochondrial impairment (w/ lactic acidosis)

o Later: hepatocellular damage (w/ lactic acidosis)
?5"
I
main
Problem
§ The typical picture of Acetaminophen (APAP)-Induced Acute Liver Injury (AIALI) is
of
-

lobulescentrilobular necrosis.
-
Si
§ Renal failure from ATN occurs occasionally, but renal failure w/o liver failure is rare
-

1943.
---
Risk factors for acetaminophen toxicity
1. Pts on enzyme inducers drugs e.g. many anti-epileptics and rifampicin (Ó activity of
CYP450). -

2. Pts w/ malnutrition, prolonged fasting, anorexia, and cachexia bec glucuronidation is

-
=>

dependent on carbohydrate stores. -

3. Alcoholics and Pt w/ HIV → Ô GSH stores.

 Clinical features
§ Suspected paracetamol intoxication in Pts w/ altered mental status + early lactic acidosis
t
ederted
- =

Clinical phases of acute paracetamol overdose LI

2
-
②
mit see
in

Phase 1 (<24 hs) ↓96

§ Asymptomatic but may have NV, abd discomfort s absoration
-

Phase 2 (1-3 ds) § Rt upper quadrant tenderness is common 195 ->

-
Se

Er
§ Hepatotoxicity defined as ALT or AST >1000 IU/L (ALT/AST ↑ rapidly to
-
-53
peak at 48-72
factor
coagulation
hs, rapidly return to nl in survivors). S

-v
->

§ ↑ PT, INR (sensitive markerconsitivia

of hepatic injury) and Bilirubin w/in hrs.
i inmetabolism -1jw-
§ Renal failure suggested by loin pain, hematuria and proteinuria
=> - ->
-

Phase 3 (3-4 ds) § In very severe cases, fulminant acute hepatic failure (↑ ALT/AST,
- -
- -

- coagulopathy w/ bleeding, jaundice, hepatic encephalopathy, and multiple

Cayulation organ failure). 55-35
-
b
LiverbalingwrecV
-

e. § Death may occur bilirubin. 50j

detoxificati S-
Phase 4 (4-14 ds) § Recovery phase (hepatic structure and function return to normal)
-
-
-
 INVESTIGATIONS dis
gis,
i
Screening tests in deliberate self-poisoning:
Side Si
-

j= =

§ 12-lead ECG and BGL

§ 'screening' paracetamol level is not useful following deliberate self-poisoning 3 file
Recordechet
-
Specific investigations as indicated ②
-' e
=>
in

§ Initial investigations according to time from paracetamol ingestion:

Labs
-

:
Time after paracetamol ingestion

:
t
Serum paracetamol
si
⑤
s! is
->

level;g';
<8 hssoon to Possible
As
At 4 hs or ASAP
>
8-24 hs
At presentation
>24 hs
-

S
i9s-
Transaminases (ALT/AST) ingestion
-
- At presentation and at end of
- ~
-

20-h NAC infusion

->
A At presentation
INR/PT - -
-

**
-
Creatinine and urea - NA 6.
-
Glucose - -
ABGs (early and late lactic - -
acidosis)
 Management of acetaminophen (APAP) poisoning
§ Record time of ingestion as accurately as possible.
§ Record time of drawing blood for paracetamol levels precisely in notes and on blood
- -

Rood sample
= -

bottles and forms.

- D

§ Risk of AIALI following single acute ingestion-

-
w/out NAC is predicted by plotting a serum
-

paracetamol level taken 4-15 hrs on Rumack–Matthew nomogram. If serum level above
-

damaged
bt0 risk of liver
the relevant line Ò start antidote Rx. assess
t
>

§ AIALI dose is >10 g or >200 mg/kg (75mg/kg in high-risk groups)&

in adults and ³250 mg/kg
> =-
in children. toxcity > 4 y >
->AIALl -
long RISK.
§ In obese Pts (>110kg) calculate toxic dose in mg/kg, and NAC dose, using BW of 110kg,
rather than Pt’s actual BW i.e. calculate w/ 110kg even if Pt BW is higher than that.
⑪ is t
&
-

liness
s5s
NAC line
je

L
O ⑧
-
S Graph not reliable
=>

Nomogram for assessing hepatotoxic risk following acute ingestion of acetaminophen

e
-
 os. ?

MANAGEMENT

Resuscitation, supportive care and monitoring

-

§ Resuscitation required only in:

o coma due to massive acute ingestion (>500 mg/kg),
Earne
zu o delayed
nee
presentation w/ established hepatic failure.
§ General supportive care and monitoring measures
§ Pts w/ rising hepatic aminotransferase levels and INR>2.5 should have 4-hourly

St
recording of vital signs and BGL, and close monitoring of fluid balance. -

&
Decontamination geord 5 S.
-

§ Oral-activated charcoal may be effective in cooperative adult who presents w/in 1st h
following overdose (but not in small children). >
- -
9g"
 & after ingestin
Acetaminophen antidotes first

liver
1. N-Acetylcysteine (NAC) to

Possible Mechanism of action: as sulfhydryl donor causes

gi 1. ↑ glutathione availability ↳ domain in sulfur
S-GSH
-

Monogram,
-

2. Direct binding to NAPQI

e

3. Supplying inorganic sulfate

is
single
4. Reduction of NAPQI back to paracetamol. ~

-
Toxicological indications -

1. Acute paracetamol overdose (plasma level OVER nomogram Tx line)

2. Empirical use when time of ingestion or serum level unknown -

3. Repeated supratherapeutic paracetamol ingestion (staggered)

ofParisen4. Fulminant hepatic failure → immediate IV NAC
Administration
i § NAC: 150 mg/kg in 200 mL G 5% IV over 15 min → 50 mg/kg in 500 mL G 5% IV over 4
=

hs → 100 mg/kg in 1000 mL of G 5% IV over 16 hs.

=>

*
infusion
§ Standard Tx duration is 20.25 hrs.D

!
-

§ Infusion continued beyond 20 hrs in Pts

-
I":
w/ late presentation, staggered overdose, or
biochemical evidence of hepatotoxicity.
detoxic ds
tissues
[35
Therapeutic end points:
• Absent or resolving hepatotoxicity as determined by transaminases
Adverse drug reactions and management:
§ Anaphylactoid reactions (10-50%) → HoTN, flushing, rash, angio-edema
o Occur during or shortly after initial dose (→ careful monitoring)
o Tx is oral H1-blocker. anymast
o if severe reaction → ceased infusion and restarted at a lowest rate as soon as sx improved
:.
-

2. Methionine (2nd line) &sor

§ Rarely needed, useful in Pts who refuse IV Tx or if NAC is not available.
§ Given orally. No significant AEs.
§ Not used in Pt w/ vomiting or presented > 8hr after ingestion bec it is less effective than
-
NAC.
=>

§ Ineffective in Pts treated w/ activated charcoal.

8,
-
-
-s

S -
-
 -ingestin
<1 h post OD 1–8 hs post OD >8 hs-24 OD or unknown
=>°@> >24 hs or unknown
AlS
gr
-

*
Activated charcoal
- -
" Serum paracetamol Immediate NAC infusion
(In cooperative adult - -

=- w/in 4–8 hs of Initiate NAC infusion if

Pts who ingested >10 -

ingestion Serum paracetamol § >10g or >200mg/kg the

g or >200 mg/kg)
+ gysy' and ALT ingested or Abo
in

Plot paracetamol level

+ § Paracetam detectable
abnormal
o g

Plot paracetamol level § or abnl labs

on nomogram
- on nomogram
-
§ or Pt symptomatic
O

C UNDER nomogram OVER nomogram OVER nomogram UNDER nomogram

Tx line Tx line Tx line Tx line confair

- High

-
Initiate 20-h Continue NAC infusion Measure ALT level
No Tx

-
NAC infusion -

zoh
mee Measure ALT->
at end C
Normal
2i of 20-h NAC infusion
STOP NAC
Stop NAC infusion Normal
-

No Tx required
No further ALT level -
-

Management flow chart for investigation High

-S
R
I

acute paracetamol exposure

-

Continue NAC and monitor ->

Zoh
-
 plastic
Liver transplantation -

High-risk criteria for fulminant hepatic failure that need transfer to a liver transplant service:
one
1. INR >3.0 at 48 hs or >4.5 at any time tim
2. Oliguria or creatinine >2.26 mg/dL
3. Acidosis (pH <7.3 after resuscitation) &
4. Systolic BP <80 mmHg >S
5. Hypoglycemia
6. Severe thrombocytopenia criticia
7. Hepatic encephalopathy of any degree.

xX
Grade I • Trivial lack of awareness • Shortened attention span
• Euphoria or anxiety • Impairment of addition or subtraction

X
Grade Il • Lethargy or apathy • Obvious personality change
• Disorientation for time • Inappropriate behavior
Grade Ill • Somnolence to semi-stupor • Gross disorientation
• Responsive to stimuli • Bizarre behavior
• Confused
Grade IV Coma
X
 29:55 Modified-release Paracetamol Formulations
monogram
Combination of immediate-release and delayed-release layers w/ ↑ total dose per tablet →
--

delayed absorption and biphasic release and elimination.

§ General rule: single paracetamol level insufficient, 2 timed paracetamol levels at least 4
hs apart plotted on paracetamol Tx nomogram is needed. If either level is above Tx line,
this is judged to be a risk of hepatotoxicity.
5, 505, --

Staggered overdose Paracetamol Ingestion

-

§ Standard nomograms do E not apply

§ GI decontamination
-
not indicated
-

§ Clinical features of hepatitis

o If present → NAC infusion immediatelyS4 s
infinio,"
o If absent → follow up with paracetamol level and ALT/AST