MANAGEMENT OF POISONING

SECONDARY TO HEPATOTOXINS
PARACETAMOL, IRON, ZINC PHOSPHIDE

Nowell Benedict C. Catbagan, MD, FPCP

BGHMC Poison Control Unit

Training Workshop on the Management of Toxic Substances Exposure at the Field Level
September 19-20, 2019
Davao City
OBJECTIVES
To describe briefly the pathophysiology behind
hepatotoxic substances
To elaborate on the symptomatology and effects of
intoxication secondary to hepatotoxic agents
To discuss the essentials of management of intoxication
secondary to hepatotoxic agents at the field level
LIVER
Main detoxifying organ of the body
 Synthesis of albumin, clotting factors & bile
acids
 Responsible for glycogen synthesis, storage a nd
breakdown
 Most biotransformation reactions lead to
detoxification but occasionally compounds
with greater toxicity are produced
LIVER

Hepatic lobule: basic

structural and functional
unit
HEPATOTOXINS: PRIMARY
MECHANISMS OF TOXICITY
HEPATOTOXINS: PRIMARY
MECHANISMS OF TOXICITY
HEPATOTOXINS: PHASES OF
TOXICITY
HEPATOTOXINS: END ORGAN COMPLICATIONS

Hypoprothrombinemia
Hypoglycemia
Liver failure
Hepatic Failure
HEPATOTOXINS:
PARACETAMOL/ ACETAMINOPHEN
PARACETAMOL
OTC analgesic and anti-pyretic
Variety of dosage forms:
Tablet
Syrup
Rectal suppository
Intravenous
2017 NPMCC Census: Paracetamol – Top
drug involved among Poisoning Cases
secondary to Pharmaceutical Agents
PARACETAMOL TO NAPQI

 90% undergoes hepatic conjugation

→ inactive metabolites →
eliminated in urine
 Glucoronidation (40-67%)
 Sulfation (20-46%)

 5% oxidized by CYP2E1 →
NAPQI (N-acetyl-p-
benzoquinonimine) → combines
with Gluthathione (GSH) →
nontoxic cysteine or mercaptates →
urine
PARACETAMOL TO NAPQI
SATURATED
Overdose → NAPQI
formation > GSH supply →
formation of protein adducts →
metabolic cascade → hepatic
cell necrosis → liver failure
Centrilobular necrosis more DEPLETED
profound due to large
concentration of oxidative
metabolism in these areas and
less gluthathione present
PARACETAMOL: HOW MUCH IS TOO MUCH?

Maximal therapeutic dose:

Adults: 4g/day
Pedia: up to 75 mg/kg/day
Toxic Dose:
Single intake of 150 mg/kg
Repeated Supratherapeutic Ingestion: >150 mg/kg/day or 6-8g/day
PARACETAMOL POISONING:
MANIFESTATIONS PER PHASE

Phase 1 (0.5-24 hrs) – Quiescent

Phase
Anorexia
Nausea/ Vomiting
Pallor
Diaphoresis
Patient and LFT’s may appear normal
PARACETAMOL POISONING:
MANIFESTATIONS PER PHASE

Phase 2 (24-72 hrs) – Onset phase

Symptomatology of phase 1 becomes less
pronounced
RUQ pain  hepatic damage
Blood chemistries become abnormal, with
elevation of liver enzymes and bilirubin
Universally seen 36 hrs post exposure
Prothrombin time is prolonged
Renal function may begin to deteriorate
PARACETAMOL POISONING:
MANIFESTATIONS PER PHASE

Phase 3 (72-96 hrs) – point of maximum

hepatotoxicity
Characterized by sequelae of hepatic necrosis.
Coagulation defects, jaundice, renal failure and
myocardial pathology
Liver biopsy at this time reveals centrilobular
necrosis
GI s/s may re-appear
Death is related to hepatic failure and frequently
preceded by anuria and coma
PARACETAMOL POISONING:
MANIFESTATIONS PER PHASE

Phase 4 – Recovery Phase

If the damage done during phase III
is not irreversible, complete
resolution of hepatic dysfunction
will follow
Hepatic regeneration, which
generally takes several days to a
few weeks
PARACETAMOL POISONING: DIAGNOSIS
Serum paracetamol levels
Blood specimen best taken at least 4 hrs post
exposure
Result compared to the Rumack Matthew
nomogram
If serum APAP above treatment line  NAC
treatment recommended
If serum APAP below treatment line  NAC
may not be given (hepatic toxicity unlikely)
PARACETAMOL POISONING: DIAGNOSIS

Other lab tests CBC, platelet count

ABG
AST, ALT
BUN, Crea
AST 1000 IU/L  NAC therapy
Serum phosphorus
Repeat serially
Hepatitis profile
PT
Repeat serially
Imaging: UTZ, CT scan, MRI
Serum electrolytes Liver biopsy
PARACETAMOL POISONING: MANAGEMENT
PARACETAMOL POISONING:
MANAGEMENT

 Antidote: N-Acetylcysteine
 Precursor for sulfate in sulfation process
 Precursor for glutathione
 Glutathione substitute
 Reduction of NAPQI to non-toxic
APAP
 In later stages
 Anti-oxidant
 Improves microcirculation
 Improves oxygen delivery and extraction
PARACETAMOL POISONING:
N-ACETYLCYSTEINE

 Most effective if given within 10 hrs post

exposure
 Indications:
 Serum level unknown, and:
 Total amount ingested >150 mg/kg
 Symptomatic patient
 Abnormal LFTs (AST > 1000 iu/L)

 Serum level is known and above the treatment

line using the Rumack Matthew nomogram
 4 hrs post exposure: 100 ug/ml or more
 8 hrs post exposure: 50 ug/ml or more
 12 hrs post exposure: 30 ug/ml or more
PARACETAMOL POISONING:
N-ACETYLCYSTEINE (INTRAVENOUS)

 Test dose: 0.1 ml in 0.9 ml D5W IV

 May give Diphenhydramine 1 mg/kg IV if patient with high risk for hypersensitivity
 Dosing:
 Phase 1: 150 mg/kg in 200 ml D5W for 1 hour
 Phase 2: 50 mg/kg in 500 ml D5W for 4 hours
 Phase 3: 100 mg/kg in 1000 ml D5W for 16 hrs
 Repeat Phase 3 NAC dosing if patient remains symptomatic, LFT’s remain elevated

 Pediatric: same dosing, but adjust diluent volume

 X = weight in kg/70 x amount of diluent (ml) as per adult dose
PARACETAMOL POISONING:
N-ACETYLCYSTEINE (ORAL)

Preferably use NAC Powder

Effervescent - large doses can
cause UGIB
Dosing:
Loading: 140 mg/kg
After 4 hrs: 70 mg/kg every 4
hours, for an additional 17 doses,
to give a total dose of 1330
mg/kg
PARACETAMOL POISONING:
N-ACETYLCYSTEINE (ORAL)

 Can be mixed with soft

drink/juice to enhance palatability
 Repeat oral dose or contemplate
IV If any dose is vomited within
one hour of administration
 Antiemetics (eg, metoclopramide,
or ondansetron) should be used to
ensure absorption
PARACETAMOL POISONING: MANAGEMENT
HEPATOTOXINS:
IRON
IRON
An element that plays a
versatile and critical to the
functioning of multiple organs
It is principally found
incorporated into hemoglobin
in erythrocytes.
IRON
Commonly seen in MV +
mineral formulations, OCP’s
Commonly used in the
treatment of Fe deficiency
anemia or as a nutritional
supplement
IRON
Absorption: occurs in the ferrous state, through the duodenum and
upper jejunum
Iron uptake increases from 10-35% to 80-95% in deficiency state
Bound to transferrin as it is transported to target tissues
Majority of iron  reticuloendothelial system and hepatocytes 
stored as ferritin
Some ferritin  hemosiderin or incorporated into hemoglobin and
cytochrome oxidase
IRON
Excretion: Primarily through exfoliation of GI
mucosal cells (1-2 mg/day) or menstrual blood loss
The body is poorly equipped to handle excessive
amounts of iron
Regulation of iron absorption does not occur in the
presence of excessive iron ingestions
IRON: HOW MUCH IS TOO MUCH?

Toxic dose of elemental iron: > 20 mg/kg

Normal serum iron (TSI): 50-150 ug/dl
Serum iron > 500 ug/dl necessitate clinical
intervention (action level)
ACUTE IRON TOXICITY:
PATHOPHYSIOLOGY

Generates oxidative stress → ↑ ROS → loss of cellular

integrity and tissue injury
Inhibits mitochondrial oxidative phosphorylation → ↑
unused H+ → metabolic acidosis
Excessive iron is directly toxic to GI mucosal cells → ↑
iron absorption
Iron also inhibits thrombin formation  ↑ bleeding
ACUTE IRON TOXICITY: STAGE 1
Initial Period – 0 to 6 hours
Nausea, vomiting, abdominal pain, diarrhea →
dehydration
GI ulceration, necrosis may occur → GI bleeding
The absence of GI S/Sx in the first 6 hours post
ingestion essentially excludes severe Iron toxicity
ACUTE IRON TOXICITY: STAGE 2

Latent Stage – 6 to 24 hours

Ongoing cellular organ toxicity without overt
manifestations
GI symptomatology usually resolves
Lethargy, tachycardia, metabolic acidosis
ACUTE IRON TOXICITY: STAGE 3

“Shock” Stage – 12 to 24 hours

Shock may be from hypovolemia, vasodilation or poor
cardiac output
CNS – lethargy, hyperventilation, seizures, coma
ACUTE IRON TOXICITY: STAGES 4 AND 5

Hepatotoxicity Stage – 2 to 3 days

Secondary to iron uptake by the RES of liver →
oxidative damage
Late Stage – 2 to 8 weeks
Gastric outlet obstruction secondary to strictures and/or
scarring
 ACUTE IRON POISONING: DIAGNOSIS

Suspect Iron
toxicity with
potential
exposures of 20
mg/kg or more of
elemental iron
ACUTE IRON POISONING: DIAGNOSIS
Radiography
Adult tablets generally with
higher iron content hence
consistently radiopaque
Liquid iron and chewable
tablet preparations are
typically not radiopaque
ACUTE IRON POISONING: DIAGNOSIS
ABG – Metabolic Acidosis
Serum electrolytes
CBC
Anemia sec to GI Blood loss
↑ WBC > 15
CBG – hyperglycemia
PT/PTT - rule out coagulopathy
ACUTE IRON POISONING: DIAGNOSIS

Total Serum Iron (TSI)

Best done between 3 to 5 hrs post exposure
300 to 500 ug/dL – usually with significant GI toxicity and
modest systemic toxicity
500 to 1000 ug/dL – with significant morbidity and
mortality
ACUTE IRON POISONING:
MANAGEMENT
ABC’s
Put patient on NPO. Give intravenous fluids.
Adult: D5 0.9NaCl or AR 1 liter x 8 hrs
Pedia: D5 0.3NaCl or AR according to KBW
Insert nasogastric tube cautiously and do gastric lavage with:
2% Na Bicarbonate solution: dilute 2 vials of 8.4% NaHCO3 (10
ml/vial) in 1 li water
Alternative: Baking Soda: 1 tbsp in 1li water
ACUTE IRON POISONING:
MANAGEMENT
Give antacids: aluminum-magnesium hydroxide or H2 blocker
Refer for emergency endoscopy
If with signs of acidosis: Start 8.4% sodium bicarbonate at 1
mEq/kg/dose IV or based on acid-base deficits
If with signs of hepatic failure: N-acetylcysteine may act as an anti-
oxidant and hepatic protectant  use Paracetamol protocol
If with renal failure/refractory metabolic acidosis: contemplate
Renal referral for Hemodialysis
ACUTE IRON POISONING: ANTIDOTE

Deferoxamine
Specific free iron chelator of high affinity and specificity
Does not chelate iron present in transferrin, hemoglobin,
hemosiderin or ferritin
Can also reach intracytoplasmic and mitochondrial free iron,
thereby limiting intracellular iron toxicity
MOA: Deferoxamine + Fe3+ → ferrioxamine complex →
excreted to kidneys → “vin rose” color (reddish brown)
ACUTE IRON POISONING:
DEFEROXAMINE
Indications for deferoxamine treatment
Peak serum iron concentration >500 mcg/dL
Significant clinical manifestations: lethargy, coma, hypovolemia,
metabolic acidosis, coagulopathy
(+) abdominal radiograph for tablets or capsules despite
gastrointestinal decontamination
Peak serum iron concentration between 350-500 mcg/dL, AND
presence of persistent vomiting, diarrhea, severe abdominal pain
Amount of iron ingested unknown or amount ingested >20 mg/kg and
TSI is not available
ACUTE IRON POISONING:
DEFEROXAMINE
Dose:
10-15 mg/kg/hr constant infusion
Alternatively: 10-15 mg/kg in 100 ml D5W to run for 1
hr, every 6 hrs
Ex: 50 kg BW = 500 mg (1 vial) in 100 ml D5W to run for
1 hr, every 6 hrs
Max Dose: 6 gms in 24 hrs
Adverse effect: Hypotension, ARDS
ACUTE IRON POISONING:
DEFEROXAMINE

Check for “vin rose” color

change post Deferoxamine
administration
 Evidence of ongoing iron
chelation
ACUTE IRON POISONING:
DEFEROXAMINE
Indications for
deferoxamine termination
 Serum iron concentration below 150
mcg/dL
 24 hours after return of normal urine
color (if vin rose colored initially)
 Absence of radio-opaque formulation
(if initially present)
 Resolution of clinical signs and
symptoms of systemic iron poisoning
ACUTE IRON POISONING: MANAGEMENT OF
OTHER PROBLEMS
HEPATOTOXINS:
ZINC PHOSPHIDE
ZINC PHOSPHIDE
 Active component in Agricultural
Rodenticides
 Other phosphorus containing
substance: Firecrackers,
Fireworks
 Usually in powders or pellets
 Contact with water  release of
phosphine gas
ZINC PHOSPHIDE: MECHANISM OF TOXICITY
 Phosphine gas is the toxic component
 MOA: Phosphine blocks mitochondrial cytochrome c oxidase
 ↑ free radical formation → lipid peroxidation
May lead to methemoglobinemia
Restrict O2 use - ↑ oxidative stress; give only once with frank hypoxemia
 Rapid toxicity within 30 minutes post ingestion → death in 6 hours
 Death faster if ingestion from fresh, unopened tablets
Opened packets → atmospheric moisture ↓ potency of tablets
 Ingestions of 500 mg or more are often fatal
ZINC PHOSPHIDE: CLINICAL
MANIFESTATIONS
Stage 1 – Gastrointestinal Phase (1-8 hrs post exposure)
vomiting, hematemesis
esophageal and gastric perforation (caustic injury)  shock with
peripheral cardiovascular collapse
Cyanosis and pallor
Delirium, convulsion, coma and death within 6- 48 hours
Early hypoglycemia is a bad prognostic sign
ZINC PHOSPHIDE: CLINICAL
MANIFESTATIONS

Stage 2 – Quiescent Phase (8th hour to several days after)

patient is symptom free or has mild symptoms such as nausea,
anorexia, disagreeable taste in the mouth
Hypotension
cyanosis mainly from methemoglobinemia
ZINC PHOSPHIDE: CLINICAL
MANIFESTATIONS

Stage 3 – Phase of Systemic Toxicity

Jaundice and profound hypoglycemia
Protracted vomiting, hematemesis, melena
Metabolic acidosis
Hepato-renal failure
ZINC PHOSPHIDE: DIAGNOSTICS
 CBC, Plt ct, Typing
 CXR
 12-L ECG
 ABG’s
 RBS/BUN/Crea/AST/ALT/Serum elec, Ca+, Mg
 U/A
 Serum lactate - ↑
 CK-MB, LDH, Trop T
 Filter paper test for methemoglobinemia
ZINC PHOSPHIDE: DIAGNOSTICS
 CBC, Plt ct, Typing
 CXR
 12-L ECG
 ABG’s
 RBS/BUN/Crea/AST/ALT/Serum elec, Ca+, Mg
 U/A
 Serum lactate - ↑
 CK-MB, LDH, Trop T
 Filter paper test for methemoglobinemia
ZINC PHOSPHIDE:
METHEMOGLOBINEMIA

 Methemoglobinemia - the iron atom in

hemoglobin loses one electron to an
oxidant, and the ferrous (Fe 2+ ) or
oxidized state of iron is transformed into
the ferric (Fe 3+ ) state  RBC unable
to take up oxygen or to release oxygen
already attached to it  cellular hypoxia
 Clinical manifestation: cyanosis that is
unresponsive to oxygen therapy
ZINC PHOSPHIDE: FILTER PAPER TEST FOR
METHEMOGLOBINEMIA

 Chocolate brown color of blood

after phlebotomy that does not
change in the presence of oxygen.
 Drop of patient’s blood on a white
filter paper  expose to oxygen
rich air  (-) change of chocolate
brown color to bright red =
methemoglobinemia (15-20%)
ZINC PHOSPHIDE:
MANAGEMENT

 ABC’s
 AVOID giving Oxygen unless if in respiratory failure!
 Dispose patient emesis in sealed containers, DO NOT inhale!
 Wet phosphides continue to generate phosphine gas
ZINC PHOSPHIDE:
MANAGEMENT

 Decontamination – only do if <1 hr post ingestion (caustic; water

↑ phosphine gas release)
 SDAC– may be considered but of uncertain value
 Bicarb lavage – ↓ gastric HCl concentration → ↓ conversion of phosphides
to phosphine gas
 Dose: 2% Sodium bicarbonate solution: Dilute 2 vials 8.4% NaHCO3 at 10ml/vial
in 1 Li of water
 Refer for Endoscopy if with s/sx of caustic injury
ZINC PHOSPHIDE:
MANAGEMENT
 Treatment mainly supportive; no antidotes!
PPI for gastric protection
 N-Acetylcysteine – Use Paracetamol protocol!
 For Hypocalcemia
 Calcium gluconate 10% (10 mL/vial) 10 mL slow IV push for 10-15
minutes
 Maintenance dosing recommendation (Toxinz) – 100 mL of 10% solution
to 900 mL D5 containing IVF to infuse at 50mL/hr to titrate against effect
ZINC PHOSPHIDE:
MANAGEMENT
For bleeding complications
Vitamin K1
Pedia: initially at 1 mg/kg not to exceed 10 mg
Adults: empiric dose of 10 mg IV
For Methemoglobinemia
Ascorbic Acid
Adults: 500-1000 mg every 6 hours
Pedia: 10-20 mg/kg every 6 hours
Contraindicated if with rhabdomyolysis
SUMMARY
There are certain toxicants that primarily exert their deleterious
effect on the liver, an organ whose main function is
DETOXIFICATION.
 Paracetamol, Iron, Zinc Phosphide
Hepatotoxins exert their clinical manifestations in phases,
including a quiescent phase.
SUMMARY
N-acetylcysteine, an antioxidant, has a role in the management of most
hepatotoxins.
 Antidotal for paracetamol toxicity
Deferoxamine, a chelating agent, is a proven antidote for iron poisoning.
Management of zinc phosphide poisoning is mainly supportive;
medications of not fully proven value include Calcium, N-Acetylcysteine
and Ascorbic Acid for methemoglobinemia
References:
• Algorithms of Common Poisonings, 4th ed.
• Manual of Technical Guidelines in the Management of Toxic Substance Exposures at the Field Level
• Goldfrank’s Toxicologic Emergencies 9th ed.
• Past powerpoint presentations of Dr. T. Briola, Dr. L. Aguinaldo (Toxicology Consultant Physicians, Members, PSCOT)